CN115105519A - Pharmaceutical composition for treating hepatitis B and preparation method thereof - Google Patents
Pharmaceutical composition for treating hepatitis B and preparation method thereof Download PDFInfo
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- CN115105519A CN115105519A CN202110995682.4A CN202110995682A CN115105519A CN 115105519 A CN115105519 A CN 115105519A CN 202110995682 A CN202110995682 A CN 202110995682A CN 115105519 A CN115105519 A CN 115105519A
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- Prior art keywords
- geraniin
- pharmaceutical composition
- hepatitis
- rosiglitazone
- pharmaceutically acceptable
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Abstract
The application provides a pharmaceutical composition for treating hepatitis B and a preparation method thereof, and the pharmaceutical composition comprises therapeutically effective amount of geraniin or pharmaceutically acceptable salt or deuterated compound thereof, therapeutically effective amount of rosiglitazone or pharmaceutically acceptable salt or deuterated compound thereof, and a pharmaceutically acceptable carrier. The composition has synergistic effect in reducing HBV DNA, HBsAg and HBeAg, and can synergistically realize anti-hepatitis B effect.
Description
Technical Field
The application relates to the technical field of antiviral drugs, in particular to a pharmaceutical composition for treating hepatitis B and application thereof.
Background
Human Hepatitis B Virus (HBV) infection is a major public health problem worldwide. After acute hepatitis B virus infection, about 8% of hepatitis B virus still develops into chronic hepatitis B infection, and persistent HBV infection can cause cirrhosis and even liver cancer. Although the new hepatitis B infection rate is effectively controlled along with the wide popularization of hepatitis B vaccines, the population base of hepatitis B virus carriers is large, and the prevention and treatment of hepatitis B become the central importance of public health problems in China. The hepatitis B transmission pathway is mainly through vertical transmission and horizontal transmission. Vertical transmission refers to mother-to-baby transmission; horizontal transmission is primarily through the blood.
The treatment of hepatitis B is also a long-term process, and the treatment aims to inhibit or eliminate HBV to the maximum extent, relieve inflammation and necrosis of liver cells and liver fibrosis, delay and stop the progress of diseases, reduce and prevent liver decompensation, liver cirrhosis, hepatocellular carcinoma and complications thereof, thereby improving the quality of life and prolonging the survival time.
There are many hepatitis b therapeutic drugs on the market today, mainly by antiviral treatment with interferon or nucleoside analogues. As for interferon, recombinant DNA leukocyte interferon (IFN-. alpha.) can inhibit HBV replication. However, when the interferon is used for treating hepatitis B, strong adverse reactions are often accompanied, including bone marrow suppression, thyroid function influence, depression and the like.
Nucleoside analogues inhibit HBV production primarily by inhibiting reverse transcriptase activity during HBV replication, and clinically useful drugs include the following classes: lamivudine and famciclovir, such as acyclovir, adefovir, entecavir, tenofovir, foscarnet and the like, and the medicaments have certain HBV inhibiting effect.
Although these reverse transcriptase inhibitors can effectively reduce the HBV DNA level and control the HBV level of patients, they have no direct effect on the clearance of HBV cccDNA and HBsAg because the target of action is the process of RNA reverse transcription into DNA. Therefore, the seroconversion probability of HBsAg is very low in single-drug treatment of nucleoside analogue, hepatitis B cannot be really cured, and patients need to take the drug for a long time or even for life.
Under the condition of taking the above drugs for a long time, the problems of drug resistance, huge medical cost, serious side effects of the drugs and the like are a heavy burden for hepatitis B patients. The key point is that at present, no medicine can completely eliminate viruses to achieve the functional cure of hepatitis B. Therefore, the urgent need in the art is to provide a new drug for treating hepatitis b, which can eliminate HBsAg and achieve a functional cure.
Disclosure of Invention
The present application provides a pharmaceutical composition capable of simultaneously reducing HBV viral load (DNA), HBsAg and HBeAg.
Specifically, the application provides a pharmaceutical composition, which comprises a therapeutically effective amount of geraniin or pharmaceutically acceptable salt or deuteron thereof, a therapeutically effective amount of rosiglitazone or pharmaceutically acceptable salt or deuteron thereof, and a pharmaceutically acceptable carrier. The inventor of the application finds that the geraniin and the rosiglitazone can not only simultaneously reduce the capacity (DNA) of hepatitis B virus, reduce HBsAg and HBeAg, but also have synergistic effect in the aspect of eliminating hepatitis B virus.
In one embodiment, the molar ratio of (geraniin or a pharmaceutically acceptable salt or deuteron thereof) to (rosiglitazone or a pharmaceutically acceptable salt or deuteron thereof) is in the range of 1: 0.4 to 1: 15, preferably 1: 0.4 to 1: 5, more preferably 1: 0.66 to 1: 5, excluding 1: 0.66, most preferably 1: 1.4 to 1: 5, most preferably 1: 3.
in a preferred embodiment, the molar ratio of (geraniin or a pharmaceutically acceptable salt or deuteron thereof) to (rosiglitazone or a pharmaceutically acceptable salt or deuteron thereof) is 1: 3.
in one embodiment, the geraniin is prepared from a traditional Chinese medicine geranium.
In one embodiment, the geraniin is present in the pharmaceutical composition in the form of a geraniin extract, preferably an aqueous decoction or an alcoholic extract. The quality standard of the water decoction or alcohol extract is based on the content of geraniin in the water decoction or alcohol extract.
In one embodiment, the pharmaceutical composition is formulated for oral administration, more preferably in the form of a tablet or capsule.
In one embodiment, it is preferred that the pharmaceutical composition further comprises one or more additional therapeutic agents, preferably, the additional therapeutic agent is selected from at least one of interferon, pegylated interferon
. These additional therapeutic agents may be administered simultaneously with the geraniin and rosiglitazone of the present application or separately in sequence.
In one embodiment, the present application also provides the use of the above pharmaceutical composition for the preparation of a medicament for the treatment of hepatitis b. The medicament is used for reducing Hepatitis B Virus (HBV) load, HBsAg and/or HBeAg levels. Preferably, the medicament is for simultaneously reducing Hepatitis B Virus (HBV) load, HBsAg and HBeAg levels.
In one embodiment, the present application also provides a method for preparing the above pharmaceutical composition, comprising: obtaining the geraniin from the traditional Chinese medicine geraniin according to the following steps: the molar ratio of rosiglitazone is 1: 0.4 to 1: 15, the resulting geraniin and rosiglitazone are mixed in a ratio preferably ranging from 1: 0.4 to 1: 5, preferably 1: 0.4 to 1: 5, more preferably 1: 0.66 to 1: 5, excluding 1: 0.66, most preferably 1: 1.4 to 1: 5, most preferably 1: 3.
in one embodiment, the geraniin is present in the form of a geranium extract, preferably an aqueous decoction or an alcoholic extract, wherein the amount of geranium extract is determined based on the content of geraniin therein. The mode of existence of the geranium extract and rosiglitazone in the pharmaceutical composition may be determined by those skilled in the art according to the dosage form of the medicament, including but not limited to a mixture, a composition, granules, capsules, tablets, sustained release tablets, controlled release tablets, etc., as long as they can release an appropriate amount of geranium and rosiglitazone in vivo.
The technical scheme of the application has the following beneficial effects:
1. the synergistic effect of the geraniin and the rosiglitazone in combination greatly improves the anti-hepatitis B virus drug effect.
2. The geraniin and the rosiglitazone can simultaneously and effectively reduce the load of Hepatitis B Virus (HBV), the HBsAg level and/or the HBeAg level, is expected to eliminate the hepatitis B virus, cure the hepatitis B and avoid the pain of lifelong medicine taking.
3. Rosiglitazone is a known medicine, the safety and the drug property of the rosiglitazone meet the requirements, the geraniin is used as the component of the known traditional Chinese medicine, the safety is good, and the combination of the two has better drug property.
Drawings
FIG. 1 shows the results of inhibition of HBV DNA by Geraniin and rosiglitazone and their combinations.
FIG. 2 shows the results of HBsAg inhibition by Geraniin and rosiglitazone and combinations thereof.
FIG. 3 shows the results of the inhibition of HBeAg by Geraniin and rosiglitazone and their combinations.
FIG. 4 is a graph showing the results of the synergistic effect of the combination of Geraniin and rosiglitazone on the inhibition of HBV DNA.
Fig. 5 is a graph analyzing the result of the synergy of the combination of geraniin and rosiglitazone on the inhibition of HBsAg.
Fig. 6 is a graph analyzing the synergistic effect results of the combination of geraniin and rosiglitazone on the inhibition of HBeAg.
Detailed Description
The inventor of the application unexpectedly finds that the geraniin and the rosiglitazone, respective deuterides thereof or pharmaceutically acceptable salts thereof have potential activity of inhibiting hepatitis B virus, particularly have synergistic effect in combined application, have good effect on reducing the load of Hepatitis B Virus (HBV), HBsAg level and/or HBeAg level, even eliminate the effect of HBsAg and HBeAg, and can be used for treating hepatitis B. The present application is described in detail below, but it should be understood that this description is only for the purpose of better illustrating the present application, and does not in any way limit the scope of protection, which is subject to the claims.
Viral hepatitis
The etiological typing of viral hepatitis is currently recognized by five hepatitis viruses, namely hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus and hepatitis E virus, which are respectively written as HAV, HBV, HCV, HDV and HEV, and the rest are RNA viruses except the hepatitis B virus which is a DNA virus.
Hepatitis b is an infectious disease mainly caused by hepatitis b virus, and is a liver disease. Clinically, the symptoms of anorexia, nausea, epigastric discomfort, liver pain and hypodynamia are mainly manifested. Some patients may have jaundice fever and hepatomegaly with impaired liver function. Some patients can become chronic, even develop cirrhosis of the liver, and a few can develop liver cancer.
The etiological agent of hepatitis b is hepatitis b virus, abbreviated as HBV, which is DNA virus. The genome is a double-stranded, circular, incompletely closed DNA. The outermost layer of the virus is the outer membrane or coat membrane of the virus, the inner layer is the core part, and the nucleoprotein is the core antigen (HBcAg) and cannot be detected in the serum. Serum from HBsAg positive persons showed 3 particles visible under electron microscope: round and filamentous particles with a diameter of 22nm, and also less spherical particles with a diameter of 42 angstroms, also known as Dane's particles, are intact HBV particles.
The markers for hepatitis b were detected as follows: (ii) HBsAg and anti-HBs: HBsAg positive indicates that HBV is currently in the stage of infection, and anti-HBs positive for immunoprotective antibodies indicates that immunity to HBV has developed. The diagnosis basis of the chronic HBsAg carrier is that the chronic HBsAg carrier has no clinical symptoms and physical signs, the liver function is normal, and the HBsAg is continuously positive for more than 6 months. (vii) HBeAg and anti-HBe: HBeAg positive is an index of HBV active replication and strong infectivity, and the change of the detected serum from HBeAg positive to anti-HBe positive indicates that the disease is relieved and the infectivity is weakened. ③ HBcAg and anti-HBc: HBcAg positive indicates that complete HBV particle direct reaction exists, and HBV active replication is less clinically used due to the complex detection method. anti-HBc is a marker of HBV infection, and positive anti-HBc IgM indicates that in early infection, there is virus replication in vivo. HBsAg, HBeAg and anti-HBc are all positive in chronic mild hepatitis B and HBsAg carriers, and have high infectivity index and are difficult to turn negative.
Geraniin
Geranium wilfordii is a common clinical Chinese herbal medicine, and is bitter in taste, slightly pungent and neutral in nature. Has effects in expelling pathogenic wind and dampness, dredging channels and collaterals, and relieving dysentery. It is mainly used for treating rheumatic arthralgia, numbness and spasm, soreness of bones and muscles, diarrhea and dysentery, etc. Modern pharmacological research finds that the traditional Chinese medicine composition has multiple effects of resisting bacteria, diminishing inflammation, resisting viruses, resisting liver injury, relieving cough, resisting oxidation, resisting cancers and the like. Japanese scholars isolated hyperin with wide physiological activity from the herb, and doctors discovered that the water extract can improve the clinical symptoms of hepatitis B patients. The geraniin is a main active ingredient contained in the traditional Chinese medicine geranium, and has the following molecular formula:
the inventor of the application finds that when geraniin and rosiglitazone are used simultaneously, the synergistic effect on reducing HBsAg, HBeAg and HBV DNA is strong. The geraniin can exist in the pharmaceutical composition in a purified compound mode, or in a mode of various traditional Chinese medicine extracts such as geraniin water extract, geraniin alcohol extract and the like.
Rosiglitazone
Rosiglitazone (Rosiglitazone) belongs to thiazolidinediones insulin sensitizers, and the mechanism of action is related to the gamma receptor (PPAR γ) of specific peroxisome proliferator activator. The sensitivity of skeletal muscle, liver and adipose tissue to insulin is increased, the utilization of glucose by cells is improved to exert the curative effect of reducing blood sugar, the fasting blood sugar and the levels of insulin and C peptide can be obviously reduced, and the postprandial blood sugar and insulin can also be reduced.
Additional therapeutic or prophylactic agents
In some embodiments, the additional therapeutic or prophylactic agent is selected from interferon and pegylated interferon
As used herein, "treating" may refer to, for example, alleviating symptoms, prolonging survival, improving quality of life, and the like. Treatment need not be a "cure". Treatment may also refer to functional cure and elimination of hepatitis b virus.
As used herein, "reducing the Hepatitis B Virus (HBV) load" refers to reducing the amount of hepatitis B virus DNA in the blood of a patient that is detectable.
As used herein, "reducing the level of HBsAg and/or HBeAg" refers to reducing the amount of hepatitis B virus HBsAg and/or HBeAg in the blood of a detectable patient. The amount of HBsAg and/or HBeAg is often closely related to a curative effect on hepatitis B function.
As used herein, "pharmaceutically acceptable" refers to a substance that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components included in the composition.
As used herein, "carrier" refers to a relatively non-toxic substance that facilitates the introduction of the compounds of the present application into a cell or tissue.
In a preferred embodiment, the medicament is formulated for administration by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
In a preferred embodiment, the medicament is formulated for oral administration, preferably in the form of a tablet or capsule.
Route of administration
The medicaments or pharmaceutical compositions of the present disclosure are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. In certain embodiments, the medicament or pharmaceutical composition disclosed herein is administered by intravenous injection. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient. One advantage of the disclosed medicaments or pharmaceutical compositions is that they are orally bioavailable and can be administered orally.
Pharmaceutical composition
The application provides a pharmaceutical composition, which comprises therapeutically effective amount of geraniin or pharmaceutically acceptable salt or deuteron thereof, therapeutically effective amount of rosiglitazone or pharmaceutically acceptable salt or deuteron thereof and pharmaceutically acceptable carrier. The inventor finds that the geraniin and the rosiglitazone can reduce the hepatitis B virus load (DNA), reduce HBsAg and HBeAg and have a synergistic effect on the aspect of eliminating hepatitis B virus.
In one embodiment, the molar ratio of (geraniin or a pharmaceutically acceptable salt or deutero) to (rosiglitazone or a pharmaceutically acceptable salt or deutero) is in the range of 1: 0.4 to 1: 15, preferably 1: 0.4 to 1: 5, more preferably 1: 0.66 to 1: 5, excluding 1: 0.66, most preferably 1: 1.4 to 1: 5, most preferably 1: 3.
in a preferred embodiment, the molar ratio of (geraniin or a pharmaceutically acceptable salt or deuteron thereof) to (rosiglitazone or a pharmaceutically acceptable salt or deuteron thereof) is 1: 3.
in one embodiment, the geraniin is prepared from a traditional Chinese medicine geranium.
In one embodiment, the geraniin is present in the pharmaceutical composition in the form of a geraniin extract, preferably an aqueous decoction or an alcoholic extract. The quality standard of the water decoction or alcohol extract is based on the content of geraniin in the water decoction or alcohol extract.
In one embodiment, the pharmaceutical composition is formulated for oral administration, more preferably in the form of a tablet or capsule.
In one embodiment, preferably the pharmaceutical composition further comprises one or more additional therapeutic agents, preferably the additional therapeutic agent is selected from interferon, pegylated interferon. These additional therapeutic agents may be administered simultaneously with the geraniin and rosiglitazone of the present application or separately in sequence.
In one embodiment, the application also provides the use of the pharmaceutical composition in the preparation of a medicament for treating hepatitis b. The medicament is for reducing Hepatitis B Virus (HBV) load, HBsAg and/or HBeAg levels. Preferably, the medicament is for simultaneously reducing Hepatitis B Virus (HBV) load, HBsAg and HBeAg levels.
In one embodiment, the present application also provides a method for preparing the above pharmaceutical composition, comprising: the geraniin is obtained from the traditional Chinese medicine geraniin according to the following steps: the molar ratio of rosiglitazone is 1: 0.4 to 1: 15, the resulting geraniin and rosiglitazone are mixed in a ratio preferably ranging from 1: 0.4 to 1: 5, preferably 1: 0.4 to 1: 5, more preferably 1: 0.66 to 1: 5, excluding 1: 0.66, most preferably 1: 1.4 to 1: 5, most preferably 1: 3.
in one embodiment, the geraniin is present in the form of a geranium extract, preferably an aqueous decoction or an alcoholic extract, wherein the amount of geranium extract is determined based on the content of geraniin therein. The mode of existence of the geranium extract and rosiglitazone in the pharmaceutical composition may be determined by those skilled in the art according to the dosage form of the medicament, including but not limited to a mixture, a composition, granules, capsules, tablets, sustained release tablets, controlled release tablets, etc., as long as they can release an appropriate amount of geranium and rosiglitazone in vivo.
In certain embodiments, the geraniin or a pharmaceutically acceptable salt or deuteron thereof, and rosiglitazone or a pharmaceutically acceptable salt or deuteron thereof, and a pharmaceutically acceptable carrier are included in the pharmaceutical composition. The pharmaceutical compositions of the present disclosure may be formulated with conventional carriers and excipients, which will be selected in accordance with common practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and, when used for delivery by non-oral administration, are generally isotonic. All formulations will optionally contain Excipients such as those described in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. The pH of the formulation ranges from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but typically from about 3 to 4.
The formulations include those suitable for the aforementioned routes of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences (Mack Publishing co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then shaping the product as necessary.
Formulations of the present application suitable for oral administration may exist as follows: discrete units, such as capsules or tablets, each containing a predetermined amount of active ingredient; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by: the active ingredient in free-flowing form, such as a powder or granules, is compressed in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated so as to provide sustained or controlled release of the active ingredient therefrom.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Additional objects, advantages and novel features of the present application will become apparent to one of ordinary skill in the art upon examination of the following examples.
Examples
Evaluation of in vitro anti-HBV Activity of HD037 and HD040 Using PHH cells (cryopreserved human Primary hepatocytes)
1. Compound (I)
Geraniin and rosiglitazone were purchased from Shanghai ceramic Biotech, Inc. and the compound formulation method was as follows:
for the preparation of 20mM concentration, the volume of the solvent DMSO (. mu.l) is the sample mass (mg). times.purity ÷ molecular weight ÷ 20X 10 6
The control compound was entecavir (ETV, lot: P1214012; 99.0% purity) purchased from Shanghai Tantake Technology, Inc. The mother liquors of the above compounds were all at 20mM concentration and stored at-20 ℃.
2. Cells and culture media
PHH cell source: (batch number: RAS) supplied by Shanghai medicine Mingkude New drug development, Ltd
Freezing and storing a PHH culture medium: mainly a DMEM medium (Gibco cat. No. 11960051) containing 10% fetal bovine serum (FBS, Hyclon cat. No. SV3008703) and 1% penicillin-streptomycin was used for cell culture.
Freezing and storing PHH plating culture medium: mainly contains 10% of fetal bovine serum (FBS, Hyclon cat # SV3008703) and 1% of penicillin-streptomycin InvitroGRO CP Medium (BIOIVT cat # S03316), and is mainly used for cell plating.
Virus infection medium: mainly contains 1 percent penicillin-streptomycin Williams' Medium E (SIGMA goods number W1878), and is mainly used for HBV virus infection.
3. Primary reagent
The main other reagents and viruses used are shown in table 1.
TABLE 1 Main Agents and viruses
4. Experimental protocol
Plating cells and compound treatment
On day 0, the cryopreserved human primary hepatocytes were revived, and the cell density was adjusted to 6X 10 5 cells/mL and plated into 96-well plates at 100. mu.L per well (6X 10) 4 Individual cells).
On day 1, cells were pretreated by adding a culture medium with a predetermined concentration of the compound for 2 hours, and then PHH cells were infected with D-type HBV, and a culture medium with a predetermined concentration of the compound was added at the same time of infection. Blanks containing only DMSO and no compound were also set up, 3 duplicate wells tested. The final test concentrations of the test compounds are shown in table 2 and the configuration is shown in table 3.
TABLE 2 Final test concentrations of Compounds
Fresh cell culture medium containing compounds containing 2% DMSO was replaced once on days 2, 4, 6, and 8.
On day 10, supernatants were collected and the collected cell supernatants were assayed for HBeAg and HBsAg levels by ELISA and HBV DNA levels by qPCR. See table 4 for experimental procedures.
Table 3: experimental procedure
Sample detection
1) qPCR method for detecting HBV DNA content in cell culture supernatant
DNA was extracted from the cell culture supernatant according to the QIAamp 96DNA Blood Kit instructions. The content of HBV DNA was detected by qPCR method. And (3) PCR reaction: at 95 ℃ for 10 min; 95 ℃ for 15 sec; 60 ℃, 1min, 40 cycles.
2) ELISA method for detecting content of HBeAg and HBsAg in cell culture supernatant
The method refers to the kit specification, and the method is briefly described as follows: respectively adding 50 mu l of standard substance, sample and reference substance into a detection plate, then adding 50 mu l of enzyme conjugate into each hole, incubating for 60 minutes at 37 ℃, washing the plate by using washing liquor, then sucking to dry, then adding 50 mu l of premixed luminescent substrate, incubating for 10 minutes at room temperature in a dark place, and finally measuring the luminescence value by using an enzyme-linked immunosorbent assay.
Data analysis
HBV DNA inhibition (%) was (1-HBV copy number of sample of compound group/HBV copy number of DMSO control group) × 100%
HBsAg inhibition (%) was (1-HBsAg value of sample/DMSO control HBsAg value) × 100%
HBeAg inhibition (%) was (1-HBeAg value of sample/DMSO control HBeAg value). times.100%
% cell viability ═ 100% (signal value for sample-signal value for media control)/(signal value for DMSO control-signal value for media control) ×
Data analysis
The synergy of Geraniin and rosiglitazone was analyzed by the Non-Constant Combo method using the Combination Index (CI) software CompuSyn software V1.0 software.
Analysis of results
The results of the measurements are shown in tables 4-6 and FIGS. 1-6.
Referring to fig. 1 to 3, rosiglitazone and geranium were used alone to inhibit HBV DNA, HBsAg and HBeAg, respectively, and when used in combination, they had a significant synergistic effect.
To analyze the synergy more clearly, a series of data were analyzed using the Combinationindex (CI) software CompuSyn software V1.0. software, with the results shown in tables 4-6 and FIGS. 4-6.
TABLE 4 HBV DNA inhibition by test Compounds
Table 5 analysis of the HBsAg inhibition synergy of the test compounds
TABLE 6 HBeAg inhibition of the test compounds
The test results show that the combination of geraniin and rosiglitazone can effectively reduce the HBV viral load, HBsAg and HBeAg and has obvious synergistic effect. The mol ratio of the geraniin to the rosiglitazone is 1: 0.4 to 1: within 5, there is a synergistic effect or an additive effect in all three aspects of HBV DNA, HBeAg and HBsAg, that is, within this ratio range, the combination of at least two parameters of HBV DNA, HBeAg and HBsAg can play a synergistic effect.
In addition, the ratio of the two is 1: 15, there was a synergistic effect only in the inhibition of HBsAg. In the preferable range of 1: 0.4 to 1: 5, more preferably 1: 0.66 to 1: 5, excluding 1: 0.66, most preferably 1: 1.4 to 1: 5, most preferably 1: and 3, the synergistic effect and the inhibition rate are highest.
From the above results, it can be seen that the combination of a therapeutically effective amount of geraniin and a therapeutically effective amount of rosiglitazone can produce a synergistic effect.
While entecavir can only reduce HBV DNA as reported in the literature, it has no substantial effect on reducing HBeAg and HBsAg. Therefore, the combination of the geraniin and the rosiglitazone can effectively reduce HBeAg and HBsAg simultaneously compared with entecavir, thereby being expected to eliminate hepatitis B virus and achieve functional cure.
While the present application has been described with reference to particular embodiments, those skilled in the art will recognize that changes or modifications can be made to the described embodiments without departing from the spirit and scope of the present application, which is defined by the appended claims.
Claims (10)
1. A pharmaceutical composition comprising a therapeutically effective amount of geraniin or a pharmaceutically acceptable salt or deuteron thereof, a therapeutically effective amount of rosiglitazone or a pharmaceutically acceptable salt or deuteron thereof, and a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1, wherein the molar ratio of geraniin or a pharmaceutically acceptable salt or deuteron thereof to rosiglitazone or a pharmaceutically acceptable salt or deuteron thereof is in the range of 1: 0.4 to 1: 15, preferably 1: 0.4 to 1: 5, preferably 1: 0.4 to 1: 5, more preferably 1: 0.66 to 1: 5, excluding 1: 0.66, most preferably 1: 1.4 to 1: 5, most preferably 1: 3.
3. the pharmaceutical composition of claim 1, wherein the molar ratio of geraniin or a pharmaceutically acceptable salt or deuteron thereof to rosiglitazone or a pharmaceutically acceptable salt or deuteron thereof is 1: 3.
4. the pharmaceutical composition of claim 1, wherein the geraniin is prepared from a traditional Chinese medicine geranium.
5. The pharmaceutical composition of any one of claims 1-4, wherein the geraniin is present in the pharmaceutical composition in the form of a geraniin extract, preferably a water decoction or an alcohol extract.
6. The pharmaceutical composition of any one of claims 1 to 5, formulated for oral administration, more preferably in the form of a tablet or capsule.
7. The pharmaceutical composition of any one of claims 1 to 6, further comprising one or more additional therapeutic agents, preferably said additional therapeutic agents are selected from interferons, pegylated interferons.
8. Use of a pharmaceutical composition according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of hepatitis b, preferably for reducing the Hepatitis B Virus (HBV) load, HBsAg and/or HBeAg levels, most preferably for simultaneously reducing the Hepatitis B Virus (HBV) load, HBsAg and HBeAg levels.
9. A process for preparing a pharmaceutical composition according to any one of claims 1 to 6, comprising: the geraniin is obtained from the traditional Chinese medicine geraniin according to the following steps: the molar ratio of rosiglitazone is 1: 0.4 to 1: 15, the resulting geraniin and rosiglitazone are mixed in a ratio preferably ranging from 1: 0.4 to 1: 5, preferably 1: 0.4 to 1: 5, more preferably 1: 0.66 to 1: 5, excluding 1: 0.66, most preferably 1: 1.4 to 1: 5, most preferably 1: 3.
10. the method of claim 9, wherein the geraniin is present in the form of a geranium extract, preferably an aqueous decoction or an alcoholic extract, wherein the amount of geranium extract is determined based on the content of geraniin therein.
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