CN103271912A - Pharmaceutical composition with obviously reduced drug resistance and preparation method and application thereof - Google Patents
Pharmaceutical composition with obviously reduced drug resistance and preparation method and application thereof Download PDFInfo
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- CN103271912A CN103271912A CN2013101654323A CN201310165432A CN103271912A CN 103271912 A CN103271912 A CN 103271912A CN 2013101654323 A CN2013101654323 A CN 2013101654323A CN 201310165432 A CN201310165432 A CN 201310165432A CN 103271912 A CN103271912 A CN 103271912A
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Abstract
The invention relates to a pharmaceutical composition with reduced drug resistance. The composition consists of lamivudine or medicinal salt or medicinal ester or a mixture thereof and a medicinal carrier; the composition configuration is suitable to be applied once per day as a unit dose, and each dose is 300mg; and the composition is used for resisting hepatitis. The composition provided by the invention is used for reducing the drug resistance caused by adopting lamivudine to treat the patients suffering from hepatitis, hepatitis B and AIDS (acquired immune deficiency syndrome) associated hepatitis B.
Description
Technical field
The present invention relates to drug world, particularly the significantly reduced anti-hepatitis composition and method of making the same of a kind of drug resistance and its application.
Background technology
Hepatitis B virus (HBV) belongs to Hepadnaviridae (hepadnaviridae), and genome is about 3.2kb, is partially double stranded cyclic DNA.The resistance of HBV is stronger, but place 10h at 65 ℃, boiling 10min or high steam all can be with its deactivation, and oxirane, glutaraldehyde, peracetic acid and povidone iodine also have inactivating efficacy preferably to HBV.
After HBV invaded hepatocyte, partially double stranded ring-type HBV DNA was that template prolongs normal chain to repair the crack district in the normal chain with the minus-strand dna in nucleus, forms covalently closed circular DNA (cccDNA); Then, be template with cccDNA, be transcribed into the mRNA of several different lengths, as the various antigens of pregenome RNA and coding HBV, and the cccDNA half-life is longer respectively, be difficult in body, thoroughly remove (Seeger C, Mason WS.Hepatitis B virus biology.Microbiol Mol Biol Rev, 2000,64 (1): 51-68).
Existing discovering, HBV has A～I9 genotype (Tran TT, Trinh TN, Abe K.New complex recombinant genotype of hepatitis B virus identified in Vietnam.JVirol, 2008,82 (11): 5657-63), China is based on C type and Type B.The HBV genotype is relevant with the therapeutic effect of progression of disease and interferon-alpha.Compare with C genotype the infected, HBeAg serology conversion early appears in B genotype the infected, less progress is chronic hepatitis, liver cirrhosis and primary hepatoma (Chu CJ, Hussain M, Lok AS.Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.Gastroenterology, 2002,122 (7): 1756-62), and, the HBeAg positive patient is higher than the C genotype to the response rate of interferon-alpha treatment, A genotype patient is higher than D genotype (Hou J, Schilling R, Janssen HL, et al.Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-induced HBeAg clearance.J Med Virol, 2007,79 (8): 1055-63).
HBV infects and is worldwide popular, and the epidemic strength that different regions HBV infects is widely different.According to World Health Organization (WHO), about 2,000,000,000 people in the whole world once infected HBV, wherein, 3.5 hundred million people are the chronic HBV infection person, annual have 1,000,000 people to die from liver failure, liver cirrhosis and primary hepatoma (HCC) (the Ganem D of HBV due to infecting approximately, Prince AM.Hepatitis B virus infection--natural history and clinical consequences.N Engl J Med, 2004,350 (11): 1118-29).
2006, China's hepatitis B Epidemiological study shows, China 1-59 year, general crowd HBsAg carrying rate was 7.18%, child's HBsAg only is 0.96%(Liang X below 5 years old, Bi S, Yang W, et al.Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination.Vaccine, 2009,27 (47): 6550-7).Calculate about 9,300 ten thousand people of the existing chronic HBV infection person of China, about 2,000 ten thousand examples of chronic hepatitis B patient (Lu FM, Zhuang H.Management of hepatitis B in China.Chin Med J (Engl), 2009,122 (1): 3-4) accordingly.
Age during infection is the main factor that influences chronicity.Infect among the HBV person period enclosing (products) phase of giving birth to and infant, have 90% and 25%～30% will develop into chronic infection respectively, later the infected only had 5～10% to develop into chronic infection in 5 years old.
Disease mainly comprises due to the chronic HBV infection, chronic hepatitis B (comprising the negative chronic hepatitis B of HBeAg positive chronic hepatitis B, HBeAg and slight, moderate thereof or severe symptom), hepatitis b cirrhosis (comprising compensatory cirrhosis, decompensated liver cirrhosis and active stage thereof or resting stage), carrier and invisible chronic hepatitis B etc.The chronic hepatitis B patient that is in again active stage can make progress and is hepatic fibrosis, liver cirrhosis, decompensated cirrhosis and HCC.
Endanger due to the chronic hepatitis B in order to reduce and to reduce, the insider actively adopts an effective measure it is prevented and treats, with long term inhibition HBV to greatest extent, alleviate the necrosis of hepatocyte inflammation and hepatic fibrosis, delay and reduce the generation that liver loses compensatory, liver cirrhosis, HCC and complication thereof, thereby make the life better quality and prolong the time-to-live.
At present, the main treatment means of chronic hepatitis B comprises antiviral, immunomodulating, antiinflammatory and antioxidation, fibrosis and symptomatic treatment etc., wherein, antiviral therapy is crucial, as long as indication is arranged, and conditions permit, just should carry out the antiviral therapy of standard.Existing medicine comprises antiviral drugs, interferon-ALPHA, anti-nucleoside (acid) analog, Thymosin alpha 1, Chinese medicine and Chinese medicine preparation etc., wherein, the overall security of nucleoside (acid) analog and toleration are good and more in clinical practice, although that it truly has is rare, the generation of rare serious adverse reaction, as renal insufficiency, myositis, rhabdomyolysis, lactic acidosis etc.
At present, being applied to clinical anti-HBV nucleoside (acid) analog medicine comprises, lamivudine (lamivudine, LAM, its structural formula is as follows), adefovir ester (adefovir dipivoxil, ADV), Entecavir (entecavir, ETV), Sebivo (telbivudine, LdT) and the tenofovir ester (tenofovir disoproxil fumarate TDF) waits 5 kinds.
Lamivudine
The random contrast clinical trial result shows that every day, 1 oral 100mg lamivudine can obviously suppress the HBV dna level both at home and abroad; HBeAg serology conversion ratio prolongs with treatment time and improves, be respectively 16%, 17%, 23%, 28% and 35%(Lok AS when treating 1,2,3,4 and 5 year, Lai CL, Leung N, et al.Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology, 2003,125 (6): 1714-22); Horizontal the higher person of ALT before the treatment, its HBeAg serology conversion ratio is higher.The randomized, double-blind clinical trial shows that chronic hepatitis B accompanies obvious hepatic fibrosis and compensatory cirrhosis patient can delay progression of disease in 3 years, reduce the incidence rate that liver function is lost compensatory and hepatocarcinoma through lamivudine therapy.The decompensated liver cirrhosis patient also can improve liver function behind lamivudine therapy, prolong life cycle.The foreign study result shows that the curative effect of lamivudine therapy child chronic hepatitis B is similar to the adult, and safety is good.China's clinical research also shows similar clinical efficacy and safety (Yao Guangbi, Cui Zhenyu, Yao Jilu etc. the IV clinical trial phase of homemade lamivudine therapy 2200 routine chronic hepatitis Bs. Chinese hepatopathy magazine, 2003,11 (2): 103-108), and its adverse reaction rate is low, the similar placebo of safety.
But, prolong with treatment time, the ratio that viral drug resistance variation takes place the lamivudine therapy chronic hepatitis B patient increases, the drug resistance incidence rate in the 1st year, the 2nd year, the 3rd year, the 4th year of medication is respectively 14%, 38%, 49% and 66%(Lok AS, Lai CL, Leung N, et al.Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology, 2003,125 (6): 1714-22).
Hepatitis B virus (HBV) has similar route of transmission to human immunodeficiency virus (HIV), and the HIV the infected up to 90% has a serologic marker thing that was exposed to HBV in the past at least, and about 10% develops into chronic hepatitis B; Show that from the investigation of one in Shanghai the HBsAg positive rate is that to merge invisible hepatitis b virus infection ratio be 30.5% to 11.2%, HIV the infected among domestic HIV the infected.Therefore, the HIV/HBV concurrent infection can not be ignored.
2009, adult HIV the infected that the U.S. announces merges in the prophylactic treatment standard of opportunistic infection and stipulates: HIV merges HBV to be infected, if no HAART indication temporarily, the best nonreactive HIV activity of the medicine of use (as interferon, adefovirdipivoxil, Entecavir); When if patient has accepted that HAART or CD4+T cell number are low to need HAART, for avoiding HBV dependency immunoinflammatory syndrome, should comprise the also activated antiviral drugs to HBV in the HAART scheme, recommend associating tenofovir and lamivudine or emtricitabine; When need treating, HBV preferably begins HAART as early as possible.But the antiviral drugs that China has gone on the market is limited.
(acquired immune deficiency syndrome (AIDS) (AIDS) patient's life expectancy progressively prolongs for Highly active antiretroviral therapy, popularization HAART) along with the efficient anti-retroviral treatment of China.The recommendation lamivudine is the composition of medicine in the line antiviral therapy scheme in China's acquired immune deficiency syndrome (AIDS) conventional treatment, lamivudine was to HIV(dosage 300mg/ days) and HBV(dosage 100mg/ days) all inhibited, and have better toleration and a low side effect incidence rate, (the Selabe S G but its higher resistant rate merits attention, Lukhwareni A, Song E, et al.Mutations associated with lamivudine-resistance in therapy-naive hepatitis B virus (HBV) infected patients with and without HIV co-infection:Implications for antiretroviral therapy in HBV and HIV co-infected south African patients[J] .JOURNAL OF MEDICAL VIROLOGY, 2007,79 (11): 1650-1654).Reports such as Wolters, the concurrent infection person take lamivudine after the 1st year, the 2nd year HBV its resistant rate is respectively 25% and 52%(Wolters L, Niesters H, Hansen B E, et al.Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with the human immunodeficiency virus in a Dutch cohort[J] .JOURNAL OF CLINICAL VIROLOGY, 2002,24 (3): 173-181).
There are some researches show, adopt adefovir ester associating lamivudine can reduce hepatitis B patient to the drug resistance of lamivudine or adefovir ester, with effective inhibition HBV DNA, promote that ALT is normal again, but, how to improve antiviral treatment effectiveness and safety, reduce the problem that its drug resistance is still is worth research.
Summary of the invention
The pharmaceutical composition that the object of the present invention is to provide a kind of drug resistance to reduce, described compositions is made up of lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture and pharmaceutically suitable carrier, wherein, described compositions configuration is suitable as unit dose and is administered once every day, in the lamivudine active weight, each dosage is 300mg, and described compositions is used for anti-hepatitis.
In the preferred technical solution of the present invention, the unit dose of lamivudine compositions is selected from any or its combination of the multiple dosage of 10mg, 30mg, 50mg, 60mg, 100mg, 200mg, 150mg, 300mg or 3.
In the preferred technical solution of the present invention, the officinal salt of described lamivudine is selected from any or its combination of inorganic acid salt, acylate, organic alkali salt, is preferably hydrochlorate, sulfate, nitrate, hydrobromate, fumarate, phosphate, lactate, Salicylate, succinate, tosilate, tartrate, acetate, formates, benzoate, mesylate, benzene sulfonate, alkali metal salt (as sodium salt), alkali salt (as magnesium salt), ammonium salt and NR
4 +(wherein, R is C
1--4Alkyl) salt, more preferably lamivudine Salicylate.
In the preferred technical solution of the present invention; the pharmaceutically acceptable ester of described lamivudine is selected from any or its combination of the acyl group functional group substituted compound of its sulphonic acid ester, stearate or its oxathiolane 2-methylol; wherein, the non-carbonyl moiety in the acyl group functional group substituted compound of described oxathiolane 2-methylol is selected from any or its combination of hydrogen, branched alkyl, straight chained alkyl, alkoxyalkyl, aralkyl.
The present composition can be various dosage form well known in the art, and being suitable for dosage form of the present invention can be preferably oral formulations for oral formulations, external preparation or injection.Oral formulations can be selected from tablet, capsule, granule, pill, powder, drop pill, syrup, mixture, distillate medicinal water, effervescent, paste, Emulsion, medicinal tea, oral liquid, suspending agent (doing outstanding agent or suspension), Emulsion or medicinal tea etc.; External preparation is optional from gel, unguentum (emplastrum, coagulate unguentum or ointment), liniment, lotion, liniment, plaster, cream, ointment, suppository etc.; Injection can be selected from injection (injection), transfusion or freeze-dried powder injection etc.Can adopt preparation technique means well known in the art to prepare compositions of the present invention.
In case of necessity, also comprise pharmaceutically acceptable carrier in the present composition, the consumption of described pharmaceutically acceptable carrier, kind are decided according to physicochemical property and the factors such as content, preparation type of effective ingredient in the compositions.
Pharmaceutically acceptable carrier of the present invention is the conventional excipients for the preparation of above-mentioned preparation well known in the art or adjuvant.Excipient or adjuvant that oral formulations or external preparation are commonly used include but are not limited to filler (diluent), lubricant (fluidizer or antitack agent), dispersant, wetting agent, binding agent, regulator, solubilizing agent, antioxidant, antibacterial, emulsifying agent, disintegrating agent etc.Binding agent, for example syrup, arabic gum, gelatin, sorbitol, tragacanth, cellulose and derivant thereof (as microcrystalline Cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methylcellulose etc.), gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Filler, for example lactose, Icing Sugar, dextrin, starch and derivant thereof, cellulose and derivant thereof, inorganic calcium salt (as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate etc.), sorbitol or glycine; Lubricant, for example micropowder silica gel, magnesium stearate, Pulvis Talci, aluminium hydroxide, boric acid, hydrogenated vegetable oil, Polyethylene Glycol; Disintegrating agent, for example starch and derivant thereof (as carboxymethyl starch sodium, Explotab, pregelatinized Starch, modified starch, hydroxypropyl starch, corn starch etc.), polyvinylpyrrolidone or microcrystalline Cellulose; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.
Excipient or adjuvant that injection of the present invention is commonly used include but are not limited to: antioxidant, for example sodium sulfite, sodium sulfite, sodium pyrosulfite, dibutyl benzoic acid etc.; Antibacterial, for example 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol; Regulator, for example hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate and buffer agent phosphoric acid dioxy sodium and sodium hydrogen phosphate; Emulsifying agent, for example Tween-80, do not have that sour Pyrusussuriensis is smooth, pluronic gram F-68, lecithin, fabaceous lecithin; Solubilizing agent, for example tween 80, bile, glycerol etc.
In addition, also active component can be mixed by its preparation requirement with pharmaceutically acceptable slow controlled release carrier, again according to the preparation method of sustained-release preparation well known in the art, as adding the blocker coating or with making micropill after the active principle microcapsulesization again, as slow-release micro-pill or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the coating blocker etc. of mixing, described oil any or its combination that agent is selected from glyceryl monostearate, castor oil hydrogenated, Dormant oils, polysiloxanes or dimethyl siloxane of mixing; Described hydrophilic colloid is selected from any or its combination of sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, PVP, arabic gum, tragcanth or carbopol; Described coating blocker is selected from any or its combination of ethyl cellulose (EC), hydroxypropyl methylcellulose (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin.
Compositions of the present invention can significantly reduce lamivudine and be used for the treatment of drug resistance due to the hepatitis, especially significantly reduces the drug resistance of hepatitis B patient, particularly significantly reduces the drug resistance that acquired immune deficiency syndrome (AIDS) merges hepatitis B patient.
In the preferred technical solution of the present invention, described hepatitis is selected from any of patient that hepatitis B infection patient, acquired immune deficiency syndrome (AIDS) merge hepatitis B infection, is preferably Chinese patient.
In the preferred technical solution of the present invention, the dosage form of described compositions is selected from tablet, suspension, capsule, granule, pill, powder, drop pill, syrup, mixture, distillate medicinal water, effervescent, paste, Emulsion, medicinal tea, powder, injection (injection), transfusion, gel, emplastrum, plaster, cream, ointment, liniment, lotion, suppository, liniment, unguentum, coagulate any of unguentum.
In the preferred technical solution of the present invention, described administration medicining mode is oral, injection or external, is preferably oral.
The anti-HIV that the object of the present invention is to provide a kind of drug resistance to reduce merges the pharmaceutical composition of virus infection, it is characterized in that, in the lamivudine active weight, active component in the described compositions is made up of with 100-300 weight portion nevirapine (NVP) 200-400 weight portion lamivudine (3TC) or its officinal salt or its pharmaceutically acceptable ester or its mixture, 200-400 weight portion zidovudine (AZT), preferably is made up of 300 weight portion lamivudines (3TC), 300 weight portion zidovudines (AZT) and 200 weight portion nevirapines (NVP).
The object of the present invention is to provide a kind of anti-HIV for the drug resistance reduction to merge the pharmaceutical composition of virus infection, it is characterized in that, in the lamivudine active weight, active component in the described compositions is by 200-400 weight portion lamivudine (3TC) or its officinal salt or its pharmaceutically acceptable ester or its mixture, 20-40 weight portion stavudine (d4T) or its ester and 100-300 weight portion nevirapine (NVP) are formed, preferably by 300 weight portion lamivudines (3TC), 30 weight portion stavudines (d4T) or its ester and 200 weight portion nevirapines (NVP) are formed.
The object of the present invention is to provide a kind of anti-hepatitis method for compositions that drug resistance reduces for preparing, it is characterized in that, lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture with the treatment effective dose, perhaps lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture, zidovudine and nevirapine perhaps prepare lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture, nevirapine, stavudine and pharmaceutically acceptable carrier according to art processes.
Another object of the present invention is to provide lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture or its pharmaceutical composition for the preparation of the application that reduces in the chemical sproof medicine of hepatitis, wherein, in the lamivudine active weight, the configuration of described compositions be fit to according to dosing interval be administered once every day, 300mg/ time scheme successive administration.
In the preferred technical solution of the present invention, the officinal salt of described lamivudine is selected from any or its combination of inorganic acid salt, acylate, organic alkali salt, is preferably hydrochlorate, sulfate, nitrate, hydrobromate, fumarate, phosphate, lactate, Salicylate, succinate, tosilate, tartrate, acetate, formates, benzoate, mesylate, benzene sulfonate, alkali metal salt (as sodium salt), alkali salt (as magnesium salt), ammonium salt and NR
4 +(wherein, R is C
1--4Alkyl) salt, more preferably lamivudine Salicylate.
In the preferred technical solution of the present invention; the pharmaceutically acceptable ester of described lamivudine is selected from any or its combination of the acyl group functional group substituted compound of its sulphonic acid ester, stearate or its oxathiolane 2-methylol; wherein, the non-carbonyl moiety in the acyl group functional group substituted compound of described oxathiolane 2-methylol is selected from any or its combination of hydrogen, branched alkyl, straight chained alkyl, alkoxyalkyl, aralkyl.
In the preferred technical solution of the present invention, the dosage form of described compositions is selected from tablet, suspension, capsule, granule, pill, powder, drop pill, syrup, mixture, distillate medicinal water, effervescent, paste, Emulsion, medicinal tea, powder, injection (injection), transfusion, gel, emplastrum, plaster, cream, ointment, liniment, lotion, suppository, liniment, unguentum, coagulate any of unguentum.
In the preferred technical solution of the present invention, described administration medicining mode is oral, injection or external, is preferably oral.
In the preferred technical solution of the present invention, described hepatitis is selected from any of patient that hepatitis B infection patient, acquired immune deficiency syndrome (AIDS) merge hepatitis B infection, is preferably Chinese patient.
The object of the present invention is to provide a kind of lamivudine for the preparation of the application in the medicine of the anti-HIV merging virus infection of drug resistance reduction, it is characterized in that, in the lamivudine active weight, active component in the described compositions is by 200-400 weight portion lamivudine (3TC) or its officinal salt or its pharmaceutically acceptable ester or its mixture, 200-400 weight portion zidovudine (AZT) is formed with 100-300 weight portion nevirapine (NVP), preferably by 300 weight portion lamivudines (3TC), 300 weight portion zidovudines (AZT) are formed with 200 weight portion nevirapines (NVP).
The object of the present invention is to provide a kind of lamivudine for the preparation of the application in the medicine of the anti-HIV merging virus infection of drug resistance reduction, it is characterized in that, in the lamivudine active weight, active component in the described compositions is by 200-400 weight portion lamivudine (3TC) or its officinal salt or its pharmaceutically acceptable ester or its mixture, 20-40 weight portion stavudine (d4T) or its ester and 100-300 weight portion nevirapine (NVP) are formed, preferably by 300 weight portion lamivudines (3TC), 30 weight portion stavudines (d4T) or its ester and 200 weight portion nevirapines (NVP) are formed.
" medicine effective quantity " of the present invention claims " treatment effective dose " again, refer to can produce when as required therapeutic scheme is taken the therapeutic effect of wishing or the amount of aitiogenic described lamivudine compounds, the treatment effective dose of described lamivudine compounds refers to that lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture are used for the treatment of or suppress can effectively reduce the chemical sproof dosage of HBV in hepatitis, hepatitis B, the HIV/HBV concurrent infection person process.
Except as otherwise noted, percentage ratio of the present invention is mass percent.
Another object of the present invention is to provide a kind of medicine box, in the lamivudine active weight, active component in the described compositions is made up of 200-400 weight portion lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture, 20-40 weight portion stavudine or its ester and 100-300 weight portion nevirapine, preferably is made up of 300 weight portion lamivudines or its officinal salt or its pharmaceutically acceptable ester or its mixture, 30 weight portion stavudines or its ester and 200 weight portion nevirapines.
Another object of the present invention is to provide a kind of medicine box, in the lamivudine active weight, active component in the described compositions is made up of 200-400 weight portion lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture, 20-40 weight portion stavudine or its ester and 100-300 weight portion nevirapine, preferably is made up of 300 weight portion lamivudines or its officinal salt or its pharmaceutically acceptable ester or its mixture, 30 weight portion stavudines or its ester and 200 weight portion nevirapines.
Effective ingredient in compositions of the present invention or the medicine box can individually dosed, administration or administration successively in proper order.
Description of drawings
Fig. 1 HBV RT district PCR product sepharose electrophoresis result, wherein, 1 is DL2000marker, 2 is blank, 3 negative contrasts, 4 positive contrasts, the positive result of 5-23;
Fig. 2 HAART scheme (3TC+d4T+NVP) treatment HIV/HBV infects and just controls patient's variation (n=31) of back HBV blood plasma carrying capacity the year before;
Fig. 3 HAART scheme (3TC+d4T+NVP) treatment HIV/HBV infects and just controls the HBV plasma viral load virus suppression ratio (n=31) of patient after 1 year;
Fig. 4 HAART scheme (3TC+d4T+NVP) treatment HIV/HBV infects and just controls patient's situation of change (n=31) of back great three positive and small three positive patient HBV virus load the year before.
The specific embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used for explanation technical scheme of the present invention, and non-limiting essence of the present invention.
Embodiment 1The various dose lamivudine is to the drug resistance research of HIV/HBV concurrent infection person hepatitis B virus
The resistant rate of the lamivudine of HBV when research HIV/HBV concurrent infection person accepts the HAART treatment, main time point and predictor that drug resistance takes place.
(1) object of study
Acquired immune deficiency syndrome (AIDS) merges Type B viral hepatitis patient's inclusion criteria:
1. ELISA detects the HIV-1 antibody positive and confirms by Western Blot method, beginning HAART treatment;
2. before the HAART with micropartical euzymelinked immunosorbent assay (ELISA) (MEIA) detect hepatitis B two and half (HBsAg, anti--HBs, HBeAg, anti--HBe, resist-HBe) HBsAg positive person or HBsAg feminine gender be with the nest-type PRC positive person that increases;
3. comprise lamivudine (having only lamivudine to have anti-HBV activity in this scheme) in the HAART therapeutic scheme;
4. previously other researchs leave blood specimen.
Satisfactoryly be in hospital or follow up a case by regular visits to patient's 100 examples (male 70 examples, women 30 examples), positive hepatitis B 85 examples of HBsAg, invisible hepatitis B 15 examples (seeing Table 1).
According to the dose difference of lamivudine in the HAART therapeutic scheme, the patient is divided into treatment group (300mg/ days (300mg/ days lamivudine+300mg/ days AZT+200mg/ days NVP) and matched group (150mg/ days lamivudine+300mg/ days AZT+200mg/ days NVP).Wherein, treatment group, positive hepatitis B 50 examples of HBsAg, invisible hepatitis B 10 examples, totally 128 parts of blood samples (seeing Table 2); Matched group, positive hepatitis B 35 examples of HBsAg, invisible hepatitis B 5 examples, totally 82 parts of blood samples (seeing Table 2).
Physical data (n=100) during table 1HIV/HBV concurrent infection patient HAART baseline
(2) method
Leave and take the blood specimen in the HIV/HBV concurrent infection person therapeutic process, use the nest-type PRC method to detect HBV RT district.
1.HBV the extraction of DNA: 200 μ, 1 serum adds equal-volume 120mmol/L sodium caprylate, heat 100 ° C12 minute; Add that 400 μ 1 are full to close phenol-chloroform (1:l), mixing, centrifugal 20 minutes of 13000rpm; Get supernatant, add again that equal-volume is full to close phenol-chloroform (1:l), mixing, centrifugal 10 minutes of 13000rpm; Add 2.5 times of ice-cold dehydrated alcohol of volume, mixing, standing over night, centrifugal 20 minutes of 13000rpm; Abandon supernatant, add 20 μ 1ddH
2O preserves to be measured.
2. polymerase chain reaction (polymerase chain reaction, PCR) method amplification HBV DNA RT district: primer adopts document (Vincenti D, Solmone M, Garbuglia A R, et al.A sensitive direct sequencing assay based on nested PCR for the detection of HBV polymerase and surface glycoprotein mutations[J] .JOURNAL OF VIROLOGICAL METHODS, 2009,159 (1): 53-57.) Bao Dao high sensitivity nest-type PRC primer, the 1st takes turns primer is: 5 '-CCTGCTGGTGGCTCCAGTT-3 ' nt56-74 and 5 '-CRTCAGCAAACACTGTRC-3 ' nt1175-1192, the 2nd takes turns primer is: 5 '-CTCGTGGTGGACTTCTCTC-3 ' nt253-271 and 5 '-GCAAANCC CMAAAGRCCCAC-3 ' nt1000-1019, and synthetic by Shanghai biotechnology Services Co., Ltd.In 50 μ, 1 cumulative volume reaction system, carry out, add 10 * buffer, 5 μ 1,2.5mmol/L dNTP(Mg
2+) (Takara) 4 μ 1, each 2 μ 1 of upstream and downstream primer 10 μ mol/L, template DNA 5 μ 1, Taq archaeal dna polymerase (Takara) 1.25U, ddH
2O31.8 μ 1.Two-wheeled pcr amplification reaction condition is all mutually: 94 ℃ of pre-degeneration 5min; 94 ℃ of degeneration 30s, 58 ℃ of annealing 60s, 72 ℃ are extended 60s, carry out 40 circulations; 72 ℃ are extended 10min again; Last 4 ℃ of preservations.Blank (ddH is all established in each reaction
2O is template), negative control (negative blood plasma extract product), positive control.
3. electrophoresis: prepare 1% agarose gel, every hole adds pcr amplification product 6 μ 1, uses DL2000bp DNA Marker contrast, and electrophoresis is 30 minutes under the 110V voltage.Observed result under the red fluorescence scanning imaging system, product band 767bp(Fig. 1).Purification and the positive sample that checks order.
(3) result of study
Result of study adopts the Stata7.0 statistical software to carry out statistical analysis.
The experimental result comparative study of 128 parts of specimen of table 2 treatment group and 82 parts of specimen of matched group
Illustrate: the positive sample of PCR described in the table 2 refers to that HIV/HBV is merged the positive infected person anteserum's dna sample of HBsAg carries out pcr amplification and order-checking, whether has the drug resistant gene sequence by analyzing patient HBV DNA, to confirm whether the patient has drug resistance to HBV, down together.
The treatment group, 60 routine HIV/HBV concurrent infection persons, totally 128 parts of blood samples, drug resistance takes place in totally 5 examples (4 routine genotype are B, and 1 example is C) patient, 1 example occurs in the HAART baseline, 1 example behind HAART 1 year, 1 example behind HAART 2 years, 1 example two-and-a-half years behind HAART, last 1 example behind HAART 3 years, 300mg/ days initial stage therapeutic effect is better in the HAART scheme of indication HIV/HBV concurrent infection person HBV.Compare with matched group (lamivudine 150mg/ days), the drug resistance incidence rate that treatment group (lamivudine 300mg/ days) is used for the treatment of the lamivudine of HIV/HBV concurrent infection person HBV significantly reduces.
Embodiment 2The various dose lamivudine is to the drug resistance research of HIV/HBV concurrent infection person hepatitis B virus
The resistant rate of the lamivudine of HBV when research HIV/HBV concurrent infection person accepts the HAART treatment.
(1) object of study
Acquired immune deficiency syndrome (AIDS) merges Type B viral hepatitis patient's inclusion criteria with embodiment 1.
Satisfactoryly be in hospital or follow up a case by regular visits to patient's 60 examples (male 48 examples, women 12 examples), positive hepatitis B 52 examples of HBsAg, invisible hepatitis B 8 examples (seeing Table 3).
According to the dose difference of lamivudine in the HAART therapeutic scheme, the patient is divided into treatment group (300mg/ days lamivudine+30mg/ days d4T+200mg/ days NVP) and matched group (150mg/ days lamivudine+30mg/ days d4T+200mg/ days NVP).Wherein, treatment group, positive hepatitis B 28 examples of HBsAg, invisible hepatitis B 4 examples, totally 70 parts of blood samples; Matched group, positive hepatitis B 14 examples of HBsAg, invisible hepatitis B 4 examples, totally 40 parts of blood samples the results are shown in Table 4.
Physical data (n=60) during table 3HIV/HBV concurrent infection patient HAART baseline
(2) method
With embodiment 1.
(3) result of study
Result of study adopts the Stata7.0 statistical software to carry out statistical analysis.
The experimental result comparative study of 70 parts of specimen of table 4 treatment group and 40 parts of specimen of matched group
Studies show that after the dosage of lamivudine increased to 300mg/ days by 150mg/ days in the HAART therapeutic scheme, the HBV drug resistance that reduces acquired immune deficiency syndrome (AIDS) merging hepatitis B patient is had remarkable result.
Embodiment 3The HAART that contains lamivudine is used for the treatment of HIV/HBV and infects the research of just controlling the patient
Research is adopted HAART scheme (300mg/ days 3TC+30mg/ days d4T+200mg/ days NVP) the treatment HIV/HBV that contains lamivudine to infect and was just controlled the patient 1 year, the levels of replication situation of change of HBV virus in patient's body.
1, object of study
Filter out 31 routine HIV and merge the first patient of controlling (any antiviral therapy at HIV or HBV of never received before this) that HBV infects (HIV/HBV), wherein, great three positive 9 examples, small three positive 22 examples, use the HAART scheme (300mg/ days 3TC+30mg/ days d4T+200mg/ days NVP) that contains 3TC to treat 1 year to the experimenter, analyze the situation of change for the treatment of front and back patient's blood plasma HBV virus replication.
2, research method
Baseline before treatment, back 1 year (48 week) for the treatment of gather patient's vein blood respectively and isolate blood plasma to-80C preserves standby.Adopt Roche TaqMan48 instrument and Roche fluorescence quantitative RT-PCR kit detection baseline and treat blood plasma HBV carrying capacity after 1 year, the detection lower limit of this detection method is the 12IU/ml(50 copies/ml), detect lower limit and improved 20 times than present domestic HBV quantitative approach commonly used.
3, statistical method
HBV carrying capacity result is lower than to detect down and adds up according to 12IU in limited time, when being higher than upper limit of detection according to 1.1X10
8IU adds up.
Statistical analysis adopts the spss statistical software, selects t check or nonparametric analysis for use according to data, and p＜0.05 has significant difference as statistical result.
4, result of study
31 routine patients are after treatment 1 year, and blood plasma HBV carrying capacity all presents decline in various degree, does not have 1 example and occurs increasing.The median of the HBV carrying capacity of baseline is 50074IU/ml(4.70log10/ml), accepting HAART treatment at HIV after 1 year, blood plasma HBV carrying capacity median is reduced to 12IU/ml(1.08log10/ml), treat that the level of HBV carrying capacity has remarkable decline (p＜0.001) (see figure 2) before and after 1 year.
The HBV virus suppression ratio for the treatment of after 1 year is seen Fig. 3, with＜12IU/ml is standard, treats preceding 31 routine baselines all greater than 12IU/ml, and 19 examples are lower than the detection lower limit of 12IU/ml behind treatment 48w, and virus suppression ratio fully is 61.3%; With＜1000IU/ml serves as that effectively the control hbv replication is analyzed, then there are 8 examples to be lower than 1000IU/ml(before the treatment and account for 25.8%), there are 21 examples to be lower than 1000IU/ml(after the treatment and account for 67.7%), through treatment in 1 year, there is 13 routine patients' (41.9%) HBV carrying capacity to be reduced in the 1000IU/ml from being higher than 1000IU/ml.
Analyze great three positive group, small three positive group patient's HBV virus load situation of change, most of small three positive patient HBV eases down to＜12IU/ml after 1 year in treatment, the results are shown in Figure 4.
The HBV carrying capacity decline level (see Table 5) of two groups of patients before and after treatment all has significant difference, and just there is significant difference in its baseline HBV carrying capacity level itself; Virus suppression ratio result (seeing Table 6) shows that great three positive patient's HBV carrying capacity is difficult to be reduced to below the 1000IU/ML, and small three positive patient's HBV carrying capacity control better.
The carrying capacity of HBV when table 5 great three positive and small three positive patient baseline and treatment 48w (log10IU/ML, n=31)
Table 6 great three positive and small three positive patient HBV virus replication suppression ratio when treatment 48w is analyzed (n=31)
By table 5-table 6, Fig. 2-Fig. 4 as seen, the first patient of controlling of HIV concurrent infection HBV is taking the HAART medicine after 1 year that contains the 3TC scheme, and HBV plasma viral load level has obtained obvious control.The 3TC medicine suppresses limited in one's ability to the high great three positive patient's of HBV carrying capacity virus replication, but the suppression ratio of small three positive patient HBV carrying capacity is reached more than 80%.
Embodiment 4The various dose lamivudine is used for the research that resistance of hepatitis B patient HBV infects
Lamivudine (300mg/ days, 100mg/ days) treatment chronic hepatitis B patient and the contrast therapy result in 3 years of tracing observation of research various dose.
1, object of study
Screening chronic hepatitis B patient 60 examples, male 30 examples wherein, women 30 examples, 18～50 years old age.Inclusion criteria:
1. HBsAg, HBeAg and the anti-HBc positive;
②HBV?DNA≥10
5copies/ml；
3. glutamate pyruvate transaminase (ALT) 〉=2 * ULN;
4. total bilirubin (TBIL) is normal;
5. get rid of and merge hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), HIV and Epstein-Barr virus (EBV), cytomegalovirus (CMV) infection.
The patient is divided into treatment group and matched group at random, each 30 example.Two groups of patients' sex, age, route of transmission, the course of disease and the equal not statistically significant of difference (P＞0.05) such as HBV DNA, ALT level when selected.All cases meet 2005 China " prevention and treatment for chronic hepatitis B guide " diagnostic criteria.
2, Therapeutic Method
The treatment group gives lamivudine 300mg/ day; Matched group gives 100mg/ day; 160 weeks (3 years) are observed in treatment.
3, observation index
12 weeks, 24 weeks, 48 all HBV DNA negative conversion rates, HBV blood serum designated object and 1,2,3 year resistant rate.
The HBV DNA standard of turning out cloudy:＜10
3Copies/ml; The drug resistance standard: HBV DNA sun changes or raises＞10
2Copies/ml, drug resistant gene detects YVDD and the YIDD positive.
Statistical analysis adopts the spss statistical software, selects t check or nonparametric analysis for use according to data, and p＜0.05 has significant difference as statistical result.
4, result
Two groups of no difference of science of statistics of HBeAg frequence of seroconversion, and study the resistant rate (seeing Table 8) in its 12 week (12w), 24 weeks (24w), 48 weeks (48w), 60 weeks (60w) HBV DNA negative conversion rates (seeing Table 7) and the 1st year, the 2nd year, the 3rd year.
The negative conversion rate comparing result of table 7 treatment group and matched group
Annotate: compare ， ﹡ between group and represent P ﹤ 0.05
Comparative study result by table 7-table 8 is known, the HBV that lamivudine 300mg/ days, 100mg/ days all can be used for the resistance of hepatitis B patient infects, possess effectiveness and safety, for lamivudine 100mg/ days therapeutic scheme, be used for resistance of hepatitis B patient HBV infection in lamivudine 300mg/ days and not only have safety, effectiveness, and can significantly reduce its drug resistance.
Embodiment 5The preparation of lamivudine tablet
1, prescription
2, preparation
Take by weighing lamivudine, microcrystalline Cellulose, the carboxymethyl starch sodium of above-mentioned weight portion, cross 100 mesh sieves respectively; With microcrystalline Cellulose and lamivudine mix homogeneously, get compound; 50% ethanol, the hypromellose that take by weighing above-mentioned weight portion stir, and add in the above-mentioned compound as binding agent, make soft material, cross 20 mesh sieves and make granule, place that baking oven is dry below 65 ℃ must do granule; Dried granule is crossed 20 eye mesh screens carry out granulate; In granulate, add magnesium stearate, the carboxymethyl starch sodium mix homogeneously of above-mentioned weight portion, get mangcorn; Mangcorn is put on the tablet machine compacting in flakes, make 1000 of Lamy stationary slices, every contains active component lamivudine 300mg.
Claims (11)
1. the pharmaceutical composition that reduces of a drug resistance, described compositions is made up of lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture and pharmaceutically suitable carrier, wherein, described compositions configuration is suitable as unit dose and is administered once every day, in the lamivudine active weight, each dosage is 300mg, and described compositions is used for anti-hepatitis.
2. pharmaceutical composition according to claim 1, the unit dose of lamivudine is selected from any or its combination of the multiple dosage of 10mg, 30mg, 50mg, 60mg, 100mg, 200mg, 150mg, 300mg or 3 in the described compositions.
3. pharmaceutical composition according to claim 1 and 2, the officinal salt of described lamivudine is selected from any or its combination of inorganic acid salt, acylate, organic alkali salt, is preferably hydrochlorate, sulfate, nitrate, hydrobromate, fumarate, phosphate, lactate, Salicylate, succinate, tosilate, tartrate, acetate, formates, benzoate, mesylate, benzene sulfonate, alkali metal salt, alkali salt, ammonium salt and NR
4 +Salt, wherein, R is selected from C
1-4Alkyl, more preferably any of its Salicylate, sodium salt, magnesium salt.
4. according to each described pharmaceutical composition of claim 1-3; the pharmaceutically acceptable ester of described lamivudine is selected from any or its combination of the acyl group functional group substituted compound of its sulphonic acid ester, stearate or its oxathiolane 2-methylol, and the non-carbonyl moiety in the acyl group functional group substituted compound of preferred described oxathiolane 2-methylol is selected from any or its combination of hydrogen, branched alkyl, straight chained alkyl, alkoxyalkyl, aralkyl.
5. according to each described pharmaceutical composition of claim 1-3, the dosage form of described compositions is selected from tablet, suspension, capsule, granule, pill, powder, drop pill, syrup, mixture, distillate medicinal water, effervescent, paste, Emulsion, medicinal tea, powder, injection, transfusion, gel, emplastrum, plaster, cream, ointment, liniment, lotion, suppository, liniment, unguentum, coagulate any of unguentum.
6. according to each described pharmaceutical composition of claim 1-4, described compositions is for reducing the drug resistance due to the lamivudine therapy hepatitis, be preferred for reducing the drug resistance due to the lamivudine therapy hepatitis B patient, more preferably merge drug resistance due to the hepatitis B patient for reducing the lamivudine therapy acquired immune deficiency syndrome (AIDS).
7. according to each described pharmaceutical composition of claim 1-5, the patient that described compositions is used for the treatment of is Chinese patient.
8. each described preparation of drug combination method of claim 1-5, it is characterized in that, lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture with the treatment effective dose, perhaps lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture, zidovudine and nevirapine perhaps prepare lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture, nevirapine, stavudine and pharmaceutically acceptable carrier according to art processes.
9. lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture or each described compositions of claim 1-5 are for the preparation of the application that reduces in the chemical sproof medicine of hepatitis, wherein, in the lamivudine active weight, the configuration of described lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture or compositions be fit to according to dosing interval be administered once every day, 300mg/ time scheme successive administration.
10. lamivudine or its officinal salt or its pharmaceutically acceptable ester or its mixture or each described pharmaceutical composition of claim 1-5 are for the preparation of the application in the compositions of the anti-HIV merging virus infection of drug resistance reduction.
11. according to Claim 8 or 9 described application, described medicine is for reducing the drug resistance due to the lamivudine therapy hepatitis, be preferred for reducing the drug resistance due to the lamivudine therapy hepatitis B patient, more preferably merge drug resistance due to the hepatitis B patient for reducing the lamivudine therapy acquired immune deficiency syndrome (AIDS), the patient that preferred described medicine is used for the treatment of is Chinese patient.
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| CN103463449A (en) * | 2013-10-11 | 2013-12-25 | 雷会勇 | Traditional Chinese medicine composite used for treating haemorrhoids and preparation method and application thereof |
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