CN102917706A - Composition for treating chronic hepatitis B, containing clevudine and adefovir dipivoxil - Google Patents

Composition for treating chronic hepatitis B, containing clevudine and adefovir dipivoxil Download PDF

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CN102917706A
CN102917706A CN201180024843XA CN201180024843A CN102917706A CN 102917706 A CN102917706 A CN 102917706A CN 201180024843X A CN201180024843X A CN 201180024843XA CN 201180024843 A CN201180024843 A CN 201180024843A CN 102917706 A CN102917706 A CN 102917706A
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clevudine
virus
adefovir ester
adefovir
hepatitis
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李圣求
李荣春
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Bukwang Pharmaceutical Co Ltd
Gilead Sciences Inc
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Triangle Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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

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Abstract

The present invention relates to a composition for treating chronic hepatitis B, containing clevudine and adefovir dipivoxil. The combined formulation of the present invention maximizes the effect for treating diseases caused by infection of hepatitis B virus and shows a mutual inhibitory activity against a resistant virus compared with a single-component formulation.

Description

The compositions that is used for the treatment of chronic hepatitis B that contains Clevudine and adefovir ester
Technical field
The present invention relates to a kind of compositions that is used for the treatment of chronic hepatitis B, it contains Clevudine (Clevudine) and adefovir ester (Adefovir dipivoxil).Clevudine of the present invention and adefovir ester compound formulation are compared with the preparation of single component, have following effect, make the therapeutic effect maximization of hepatitis b virus infected disease, demonstrate the mutual inhibitory action to drug resistance virus.
Background technology
Hepatitis refers to that liver produces inflammation, the state that hepatocyte is damaged.The cause of disease that occurrence frequency is the highest is viral infection.Academicly, the highest hepatitis B of shared frequency in the viral hepatitis is defined as the lasting situation more than 6 months of viral surface antigen (HBsAg).Hepatitis B virus (HBV, Hepatitis B Virus) behind intracellular infection, copies, and then in blood, discharge surface antigen and be called as the HbeAg of peplos (envelope) antigen, and the virion (virion) that has kept self DNA.Therefore, above antigen is used as diagnosing the index of hepatitis.
Acute hepatitis, the clinical symptoms such as liver function reduction can be restored or fully recover in its 3-4 after hepatitis occurs month.In contrast, in the situation of chronic hepatitis, refer in liver function and the tissue examination, hepatitis continues the state more than 6 months, it is reported in the Chronic HBV carrier approximately 25% can be dead because of constitutional HCC or liver cirrhosis.
According to WHO(World Health Organization (WHO)) report, the chronic carrier of hepatitis B is about 400,000,000, and 1,000,000 above Died Of Diseases are approximately arranged every year.Especially 20% chronic hepatitis patient changed hepatocarcinoma or liver cirrhosis into and death during metainfective 10 ~ 20 years, 70% hepatitis has shown and hepatitis b virus infected dependency, therefore, conscientiously need to develop a kind of Therapeutic Method of establishment virus replication, to be used for the early treatment of hepatitis B.
The treating hepatitis B agent of having developed up to now, can not be eliminated HBV fully in body.In addition, during this kind medicament of life-time service, will inevitably produce the anomaly HBV that medicament is had resistance.
The 1-(2 ' of nucleoside series-deoxidation-2 '-fluoro-beta-L-arabinofuranosyl base) thymus pyrimidine (being designated hereinafter simply as Clevudine) is sold with the trade name of Levovir, when giving Clevudine, can reduce the cccDNA in the chronic hepatitis B patient hepatocyte, therefore, known its has the following advantages.After administration finishes, also can continue for a long time the inhibition to virus.
Adefovir ester as the antiviral property medicine, name according to the name of chemical compound nomenclature is called two (new pentane acyloxy) methoxyl groups of 9-[2-[] phosphatidyl methoxy] ethyl-adenine, it has demonstrated excellent in vivo antiviral activity as reverse transcriptase inhibitors to HIV and hepatitis B virus (HBV).The antiviral activity of above-mentioned substance can be with reference to " the infectious disease magazine " of Barditch-Crovo P etc.; 176(2): 406; 1997(J.Infect.Dis.; 176(2): 406; 1997) and Starrett etc. " Mediterranean chemistry "; 37:1857-1864(1994) (J.Med.Chem., 37:1857-1864(1994)).
Under naturalness, known adefovir ester has amorphous (amorphism) and two kinds of forms of crystallization shape (crystal), and adefovir ester is hydrolyzed by moisture, generates decomposition product matter, therefore, and the problem that existence and stability is poor.In order to solve this stability problem, (international publication number: disclose more stable pharmaceutical composition of adefovir dipivoxil WO0035460A), it contains anhydrous crystal adefovir ester and dihydrate crystallinity adefovir ester and basic excipients in the PCT patent application.
For chronic hepatitis B patient is carried out effective long-term treatment, need the administering drug combinations of anti-virus formulation.The problem of the maximum of these HBV anti-virus formulations is, behind the administration certain hour, drug-resistant virus can occur.Generally, the drug-resistant virus that is widely known by the people most is anti-lamivudine virus, is equivalent to the rtL180M variation of HBV polymerase B area part and the rtM204I/V variation of C area part.The patient is given in the situation of lamivudine, if begin to occur this drug-resistant virus, the virus concentration in the blood is increased, so that ALT/AST numerical value rises rapidly, it is dangerous that patient's state becomes, and therefore needs to use the other medicines to these drug-resistant virus sensitivities to carry out administration.So far, in the medicine that allows to sell as the treatment of chronic agent, the medicine that anti-lamivudine virus is demonstrated effect is adefovir ester.But adefovir ester is more or less not fully up to expectations aspect antiviral effect, when long term administration, the virus of drug resistance can occur adefovir ester is demonstrated, the rtA181V/T of HBV polymerase part, and the rtN236T variation is equivalent to this.Therefore, expression for the drug-resistant virus that suppresses to greatest extent specific medication is demonstrated, and effectively treat chronic hepatitis B, be to need a kind of medicine, it would be better to say that what more need is the administering drug combinations that drug-resistant virus is demonstrated mutual inhibiting medicine, and this is paid much attention to.
United States Patent (USP) the 6th, 528, in No. 515, the Therapeutic Method as the hepatitis b virus infected disease for the treatment of discloses a kind of administering drug combinations method that existing hepatitis B virus is had the medicine of antiviral effect.As an example, relate to the combination of adefovir ester and Clevudine.And disclose following content: the effect of these drug regimens, (1:1 mol ratio) is minimum when the relative concentration of Clevudine is the highest, when the mol ratio of two chemical compounds is 3:1, obtains the most excellent integral body and interacts.But, here just illustration the administering drug combinations of Clevudine with adefovir ester, do not disclose the effect of these drug regimens or the experimental result that the effect that interaction obtains is supported, and do not relate to the resistance variant viral fully.
To this, the inventor wants to develop a kind of novel compositions, and it when making the therapeutic effect maximization of hepatitis b virus infected disease, especially has the inhibitory action to the drug resistance variant viral by the administering drug combinations of HBV anti-virus formulation.
Summary of the invention
Technical problem
The object of the invention is to, a kind of pharmaceutical composition is provided, this pharmaceutical composition has following effect, makes the therapeutic effect maximization of chronic HBV infection disease, has the mutual inhibitory action to drug-resistant virus.
The method of dealing with problems
For reaching above-mentioned purpose, the invention provides a kind of compositions that is used for the treatment of the chronic HBV infection disease, it contains Clevudine and adefovir ester.
Among the present invention, the weight ratio that has prepared Clevudine and adefovir ester is the preparation of 3:1 ~ 1:1, the cell efficiency test result of said preparation shows, compare with unitary agent, Clevudine and adefovir ester compound formulation compositions, significantly improved the therapeutic effect of hepatitis b virus infected disease, and along with the concentration that improves Clevudine in the compositions, this effect is more remarkable.Especially compound formulation compositions of the present invention has demonstrated the effect that rises to the variant viral with lamivudine and adefovir ester resistance, helps therefore to illustrate that compositions of the present invention has excellent inhibitory action to variant viral.
Clevudine of the present invention and adefovir ester compound formulation, dosage in the pharmaceutics compositions that is used for the treatment of the chronic HBV infection disease, can carry out multiple adjustment according to the kind of patient's age, symptom, form of administration or medicine, Clevudine is preferably 5 ~ 100mg, more elect 10 ~ 30mg as, adefovir ester is preferably 5 ~ 30mg, more elects 5 ~ 10mg as.
In addition, compositions of the present invention can be used in the pharmaceutics and to allow the common excipient that uses etc. to be prepared, and in order to obtain high bioavailability, can adopt conventional preparation method.
The carrier that pharmaceutically allow to use of the present invention be can with the organic or inorganic carrier of active component together administration, comprise the carrier for the solid pharmaceutical formulations, such as excipient, lubricant, binding agent and disintegrating agent etc.
As preferred excipient, such as lactose, white sugar, PEARLITOL 25C, D-glucitol, corn starch, dextrin, crystallinity cellulose, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose (CMC-Na), arabic gum, dextrin, amylopectin, light anhydrous silicic acid (lightanhydrous silicic acid), synthetic aluminium silicate, aluminium silicate-magnesium etc. are arranged.
As preferred lubricant, magnesium stearate, calcium stearate, Pulvis Talci, silica gel are for example arranged.As preferred binding agent, such as polyvinylpyrrolidone, pregelatinized Starch, corn starch, sucrose, glutelin, arabic gum, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystallinity cellulose, white sugar, hydroxypropyl cellulose and hydroxypropyl emthylcellulose (HPMC) etc. are arranged.
As preferred disintegrating agent, such as Sodium Starch Glycolate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, light anhydrous silicic acid and low-substituted hydroxypropyl cellulose etc. are arranged.
The effect of invention
Clevudine of the present invention and adefovir ester compound formulation compositions are compared with unitary agent, have following effect, make the therapeutic effect maximization of hepatitis b virus infected disease, demonstrate the mutual inhibitory action to drug-resistant virus.
Description of drawings
Fig. 1 is expression Clevudine, adefovir ester, and Clevudine is hybridized (Southern Hybridization) result with the adefovir ester compound formulation to the southern blotting technique of the antiviral effect of HBV wild-type virus.
Fig. 2 is expression Clevudine, adefovir ester, and Clevudine and adefovir ester compound formulation shield imager (PhosphorImager) result to the phosphorus of the antiviral effect of HBV wild-type virus.
Fig. 3 is expression Clevudine, adefovir ester, and Clevudine and adefovir ester compound formulation are to the southern blotting technique results of hybridization of the antiviral effect of the rtM204I variant viral that is derived from the patient.
Fig. 4 is expression Clevudine, adefovir ester, and Clevudine and adefovir ester compound formulation shield the imager result to the phosphorus of the antiviral effect of the rtM204I variant viral that is derived from the patient.
The specific embodiment
Below by embodiment, the present invention is carried out more specific description.But these embodiment only are illustrations of the present invention, and scope of the present invention is not limited in this.
Embodiment 1: the tablet that contains Clevudine and adefovir ester
[component content]
The 30mg Clevudine
The 10mg adefovir ester
The 10mg Sodium Starch Glycolate
The 1mg polyvinylpyrrolidone
The 142mg PEARLITOL 25C
The 5mg Pulvis Talci
The 2mg magnesium stearate
Make adefovir ester, Clevudine, Sodium Starch Glycolate, polyvinylpyrrolidone, PEARLITOL 25C cross 18 mesh sieves and mix, make water carry out granulating after, carry out drying, so that utilize aquametry (KF method) to be no more than 2%.After dry thing crossed 25 mesh sieves, mix Pulvis Talci and magnesium stearate, use the direct compressed mixture of planar rondure drift of 8mm diameter, make the 200mg tablet.
Embodiment 2: the tablet that contains Clevudine and adefovir ester
[component content]
The 20mg Clevudine
The 10mg adefovir ester
The 10mg Sodium Starch Glycolate
The 1mg polyvinylpyrrolidone
The 152mg PEARLITOL 25C
The 5mg Pulvis Talci
The 2mg magnesium stearate
Make adefovir ester, Clevudine, Sodium Starch Glycolate, polyvinylpyrrolidone, PEARLITOL 25C cross 18 mesh sieves and mix, make water carry out granulating after, carry out drying, so that utilize aquametry (KF method) to be no more than 2%.After dry thing crossed 25 mesh sieves, mix Pulvis Talci and magnesium stearate, use the direct compressed mixture of planar rondure drift of 8mm diameter, make the 200mg tablet.
Embodiment 3: the tablet that contains Clevudine and adefovir ester
[component content]
The 10mg Clevudine
The 10mg adefovir ester
The 10mg Sodium Starch Glycolate
The 1mg polyvinylpyrrolidone
The 162mg PEARLITOL 25C
The 5mg Pulvis Talci
The 2mg magnesium stearate
Make adefovir ester, Clevudine, Sodium Starch Glycolate, polyvinylpyrrolidone, PEARLITOL 25C cross 18 mesh sieves and mix, make water carry out granulating after, carry out drying, so that utilize aquametry (KF method) to be no more than 2%.After dry thing crossed 25 mesh sieves, mix Pulvis Talci and magnesium stearate, use the direct compressed mixture of planar rondure drift of 8mm diameter, make the 200mg tablet.
Effect test example 1: Clevudine and adefovir ester compound formulation are to the antiviral effect test of HBV wild-type virus
Give anti-virus formulation in order to make the therapeutic effect maximization to chronic hepatitis B patient, need to unite.In order to confirm the antiviral effect of Clevudine of the present invention and adefovir ester compound formulation, carried out following test.
(1) transfection of viral DNA (Transfection)
In transfection approximately before 20-24 hour, with the Huh-7 cell strain on 6 orifice plates with 4 * 10 5The amount of cells/well is put into, and makes it converge (confluence) and reaches 70 ~ 80%, and cultivate.Before transforming 2 hours, from the cell of stabilisation, remove culture fluid, with the amount replaced medium in 2mL/ hole, above-mentioned culture medium is serum-free medium, and is the culture medium with Clevudine, adefovir ester or Clevudine/adefovir ester compound formulation concentration dilution separately.Then, utilize liposome (lipofectamine, hero company (Invitrogen)) to carry out transfection, so that the every hole of HVB wild type DNA is 2 μ g.Drug treating concentration is as follows.Clevudine is 0.9 μ M, and adefovir ester is 6.3 μ M, in the situation of compound formulation, uses Clevudine and adefovir ester 0.9 μ M+6.3 μ M or 1.8 μ M+6.3 μ M to process simultaneously.After the transfection 5 hours, replace with the culture fluid that treated with medicaments is crossed, per 24 hours, the culture fluid of treated with medicaments is changed.
(2) cell harvesting and HBV DNA separate
After the transfection the 4th day, use cold PBS to clean cell after, collect.Utilize cold hydroxyethyl piperazine ethanesulfonic acid cytolysis (Hepes Lysis) buffer (1%NP-40) to dissolve, after the centrifugalize, use nuclease (nuclease) to process supernatant, thereby remove the cell DNA of transfection.Use 26%PEG solution, the core protein of precipitation housing (capsid) form.Then, SDS solution and the E.C. 3.4.21.64 (ProteinaseK) of use 0.5% are processed, thereby remove housing albumen, separate the HBV DNA of enclosure interior.
(3) southern blotting technique hybridization
The HBV DNA that separates is carried out electrophoresis in 1% agarose gel, to being with electropositive nylon membrane to carry out capillary transfer (capillary transfer).On the film that shifts, with labelling 32The integral body of the gel of P--refining-length HBV fragment is carried out hydridization (Hybridization), utilize the SSC buffer solution for cleaning after, carry out sensitization at the X ray thin film.Utilize phosphorus screen imager to measure Clevudine and adefovir ester compound formulation to Clevudine separately or the antiviral effect of adefovir ester individual processing group.
Fig. 1 is expression Clevudine, adefovir ester, and Clevudine and adefovir ester compound formulation southern blotting technique hybridization (Southern Hybridization) result to the antiviral effect of HBV wild-type virus, and Fig. 2 is that phosphorus shields the imager result.
As depicted in figs. 1 and 2, adefovir ester of the present invention is compared with unitary agent with the Clevudine compound formulation, and the HBV wild-type virus is had effective antiviral effect.Particularly, the HBV wild-type virus replication rate of the matched group of will be not processing with medicine is as 100% the time, HBV wild-type virus replication rate is respectively 65.91% and 55.53% in Clevudine processed group, the adefovir ester individual processing group, and the relative replication rate that uses above-mentioned two kinds of simultaneously treated compound formulations of medicine is 37.44%.Namely, it is 62.56% that the HBV wild-type virus of compound formulation processed group copies the obstruction rate, compare with 34.09% of Clevudine individual processing group, demonstrated approximately 2 times antiviral effect, can find out that compound formulation is far superior to independent preparation to the effect of HBV wild-type virus.
Effect test example 2: Clevudine and adefovir ester compound formulation are to the antiviral effect test of HBV variant viral
As mentioned above, after the greatest problem of HBV antiviral therapy agent is the administration certain hour, drug-resistant virus can appear.The general drug-resistant virus that is widely known by the people most is anti-lamivudine virus, is equivalent to the rtL180M variation of HBV polymerase B area part and rtM204I, the rtM204V variation of C area part.As the adefovir resistant nma virus, rtA181V, the rtA181T of HBV polymerase part, the rtN236T variation is equivalent to this.The present invention utilize generally be widely known by the people most to the effective adefovir ester of anti-lamivudine virus, with to the effective Clevudine of adefovir resistant nma virus, prepared compound formulation, by the following method, the antiviral effect of the drug-resistant virus of compound formulation of the present invention has been tested.
(1) variant viral clone
In order to clone the natural drug resistance thing HBV virus of the HBV polymerase meristic variation with anti-lamivudine virus and adefovir resistant nma virus, from patient's serum, separate HBV DNA(QIAmp MinElute virus spin test kit (QIAmp MinElute Virus Spin Kit) (QIAGEN company), with the reverse transcriptase part of PCR method amplification HBV, be subcloned on the whole expression vector of wild type.Use test kit (love is pursued progress (Axygen)) that DNA has been carried out a large amount of separation.
(2) viral DNA transfection
In transfection approximately before 20-24 hour, with the Huh-7 cell strain on 6 orifice plates with 4 * 10 5The amount of cells/well is put into, and it is converged reach 70 ~ 80%, and cultivate.Before transforming 2 hours, from the cell of stabilisation, remove culture fluid, with the amount replaced medium in 2mL/ hole, above-mentioned culture medium is serum-free medium, and is the culture medium with Clevudine, adefovir ester or Clevudine/adefovir ester compound formulation concentration dilution separately.Then, utilize liposome (hero company (Invitrogen)) to carry out transfection, so that the every hole of HVB wild type DNA is 2 μ g.Drug treating concentration is as follows.Clevudine is 0.9 μ M, and adefovir ester is 6.3 μ M, in the situation of compound formulation, uses Clevudine and adefovir ester 0.9 μ M+6.3 μ M or 1.8 μ M+6.3 μ M to process simultaneously.After the transfection 5 hours, replace with the culture fluid that treated with medicaments is crossed, per 24 hours, the culture fluid of treated with medicaments is changed.
(3) cell harvesting and HBV DNA separate
After the transfection the 4th day, use cold PBS to clean cell after, collect.Utilize cold hydroxyethyl piperazine ethanesulfonic acid cytolysis buffer (1%NP-40) to dissolve, after the centrifugalize, use nuclease to process supernatant, thereby remove the cell DNA of transfection.Use 26%PEG solution, the core protein of precipitation Shell Form.Then, SDS solution and the E.C. 3.4.21.64 of use 0.5% are processed, thereby remove housing albumen, separate the HBVDNA of enclosure interior.
(4) southern blotting technique hybridization
The HBV DNA that separates is carried out electrophoresis in 1% agarose gel, to being with electropositive nylon membrane to carry out capillary transfer.On the film that shifts, with labelling 32The integral body of the gel of P--refining-length HBV fragment is carried out hydridization, utilize the SSC buffer solution for cleaning after, carry out sensitization at the X ray thin film.Utilize phosphorus screen imager to measure Clevudine and adefovir ester compound formulation to Clevudine separately or the antiviral effect of adefovir ester individual processing group.
Fig. 3 is expression Clevudine, adefovir ester, and Clevudine and adefovir ester compound formulation are to the southern blotting technique results of hybridization of the antiviral effect of the rtM204I variant viral that is derived from the patient; Fig. 4 is phosphorus screen imager result.
As shown in Figure 3 and Figure 4, adefovir ester of the present invention is compared with unitary agent with the Clevudine compound formulation, and the rtM204I variation that is derived from the patient is had effective antiviral effect.Particularly, the rtM204I variant viral replication rate that is derived from the patient of the matched group of will be not processing with medicine is as 100% the time, the variant viral replication rate is respectively 87.43% and 31.17% in Clevudine processed group, the adefovir ester individual processing group, and the relative replication rate that uses above-mentioned two kinds of simultaneously treated compound formulations of medicine is 24.49%.In addition, Clevudine concentration is increased in the compound formulation of twice, the variant viral replication rate is 13.69%, significantly reduces.That is, it is 75.51% or 86.31% that the variant viral of compound formulation processed group copies the obstruction rate, can find out, the effect of compound formulation is far superior to known to 68.83% of the effective adefovir ester individual processing of variant viral group.
Effect test example 3: Clevudine and adefovir ester compound formulation are to the antiviral effect test of chronic hepatitis B patient
Be used for effectively treating the therapeutic alliance effect of two medicaments of chronic hepatitis B patient, although it does not also have the research about the compound formulation of Clevudine and adefovir ester as being applied to clinical new treatment strategy.In order to confirm that Clevudine of the present invention and adefovir ester compound formulation to the antiviral effect of chronic hepatitis B patient, have carried out following test.
Antiviral effect test to chronic hepatitis B patient
Totally 40 patient is divided into following two groups.One group is the administration group that gives separately the 30mg Clevudine every day, and (Clevudine is organized separately to be total to 24 weeks of administration; N=20).Another group gives 30mg Clevudine and 10mg adefovir ester for uniting every day, altogether after 12 weeks of administration, stops the adefovir ester administration, and (Clevudine+adefovir ester is united group to give the administration group of 30mg Clevudine lasting every day; N=20).
Its result is, in administration during 12 week, the Clevudine separately HBV dna replication dna number of group copies (copies)/mL for-2.67log10, and Clevudine+adefovir ester is united group and copied/mL for-4.11log10, has statistical significant difference (p=0.001).In administration 24 during week, Clevudine separately group copies/mL for-4.15log10, and Clevudine+adefovir ester is united group and copied/mL for-4.97log10, has statistical significant difference (p=0.036).
This explanation is being carried out chronic hepatitis B patient when treatment at initial stage, more can strong inhibition HBV propagation than the only administration of Kerafyrm order without the administration of the Clevudine of cross tolerance+adefovir ester compound formulation.
Industrial applicibility
Clevudine of the present invention and adefovir ester compound formulation compositions are compared with independent preparation, have following effect, make the therapeutic effect maximization of hepatitis b virus infected disease, demonstrate the mutual inhibitory action to drug-resistant virus.Therefore needing especially to be suitable in the treatment of chronic hepatitis B of long-term treatment.

Claims (9)

1. a compositions that is used for the treatment of the chronic HBV infection disease is characterized in that, it contains Clevudine and adefovir ester.
2. the compositions that is used for the treatment of the chronic HBV infection disease according to claim 1 is characterized in that, it contains the Clevudine of 5 ~ 100mg and the adefovir ester of 5 ~ 30mg.
3. the compositions that is used for the treatment of the chronic HBV infection disease according to claim 2 is characterized in that, it contains the Clevudine of 10 ~ 30mg and the adefovir ester of 5 ~ 10mg.
4. each described compositions that is used for the treatment of the chronic HBV infection disease is characterized in that according to claim 1-3, and chronic HBV is drug-resistant virus.
5. the compositions that is used for the treatment of the chronic HBV infection disease according to claim 4 is characterized in that, drug-resistant virus is anti-lamivudine virus.
6. the compositions that is used for the treatment of the chronic HBV infection disease according to claim 5 is characterized in that, anti-lamivudine virus is for showing the virus of rtL180M, rtM204I or rtM204V variation.
7. the compositions that is used for the treatment of the chronic HBV infection disease according to claim 4 is characterized in that, drug-resistant virus is the adefovir resistant nma virus.
8. the compositions that is used for the treatment of the chronic HBV infection disease according to claim 7 is characterized in that, the adefovir resistant nma virus is for showing the virus of rtA181V, rtA181T or rtN236T variation.
9. each described compositions that is used for the treatment of the chronic HBV infection disease is characterized in that according to claim 1-3, and chronic HBV is the wild type hepatitis B virus.
CN201180024843XA 2010-05-18 2011-04-18 Composition for treating chronic hepatitis B, containing clevudine and adefovir dipivoxil Pending CN102917706A (en)

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KR10-2010-0046543 2010-05-18
KR1020100046543A KR20100127180A (en) 2009-05-25 2010-05-18 Compositions for the treatment of chronic hepatitis b containing clevudine and adefovir dipivoxil
PCT/KR2011/002747 WO2011145808A2 (en) 2010-05-18 2011-04-18 Composition for treating chronic hepatitis b, containing clevudine and adefovir dipivoxil

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CN116327793A (en) * 2021-06-07 2023-06-27 天津济坤医药科技有限公司 Use of clavulanine in the manufacture of a medicament for the treatment of idiopathic pulmonary fibrosis

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