CN1391482A - Therapy - Google Patents
Therapy Download PDFInfo
- Publication number
- CN1391482A CN1391482A CN99816471A CN99816471A CN1391482A CN 1391482 A CN1391482 A CN 1391482A CN 99816471 A CN99816471 A CN 99816471A CN 99816471 A CN99816471 A CN 99816471A CN 1391482 A CN1391482 A CN 1391482A
- Authority
- CN
- China
- Prior art keywords
- hepatitis
- medicated bag
- vaccine
- antiviral agent
- lamivudine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 235000020357 syrup Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/29—Hepatitis virus
- A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- 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
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2730/00—Reverse transcribing DNA viruses
- C12N2730/00011—Details
- C12N2730/10011—Hepadnaviridae
- C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
- C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
This invention provides a pharmaceutical pack comprising as active ingredients (1) an antiviral agent active against hepatitis B virus and (2) a vaccine for the prophylaxis and/or treatment of hepatitis B infection, the active ingredients being for simultaneous or sequential use. Preferred components are a nucleoside analogue as the antiviral agent, together with a hepatitis B virus vaccine which comprises a hepatitis B virus surface antigen.
Description
The inhomogeneity antiviral activity agent of the present invention relates to have anti-hepatitis B virus (HBV) active nucleoside analog or anti-HBV is as IFN-or nucleotide analog and the application of a kind of HBV vaccine in treatment is hepatitis b virus infected.
It is the great difficult problem of a class that influences global human health that chronic HBV (HBV) infects, and nowadays it is not found effective Therapeutic Method yet.The quantity of the chronic carrier of whole world HBV is estimated to surpass 300,000,000, and these people have the danger of suffering from chronic active hepatitis, sclerosis and hepatocarcinoma.
EP-A-388049 (Beecham Group p.l.c.) discloses the application of penciclovir/famciclovir in treatment is hepatitis b virus infected.All blanks of penciclovir/famciclovir comprise the salt that pharmacy is allowed in the literary composition, and the solvate that example hydrochloric acid salt and pharmacy are allowed is as hydrate.
EP-A-494119 (IAF Biochem.International Inc.) discloses 1, the 3-oxathiolane nucleoside analog, and comprising lamivudine, the application in treating hepatitis B.
The invention provides a kind of medicated bag (pharmaceutical pack), wherein comprise antiviral agent active component and (2) a kind of vaccine that is used for preventing and/or treating hepatitis B infection that (1) has anti-hepatitis B virus activity, this active component can use simultaneously or successively.
Explanation to " medicated bag " is meant a kind of packing that includes a unit dose or multiple-units dosage form active component or divides medicine device.This packing can comprise that for example, metal forming or plastic foil are such as the form that can adopt bubble-cap agent (blisterpack).This packing or branch medicine device can have the administration explanation.When hope is carried out administration to antiviral agent and HBV vaccine as two separate constituents, also can with its with, for example, the form of double pack provides.
The present invention can be used for the treatment or the prevention of hepatitis B infection.The purposes that the present invention is unique is to be used for treatment, and for example, chronic hepatitis B infects.
On the one hand, the antiviral agent in the medicated bag can be a kind of nucleoside agent.On the other hand, antiviral agent can be a kind of nucleotide agent.Be applicable to that medicament of the present invention comprises penciclovir, famciclovir, lamivudine, ganciclovir, lobucavir, adefovir, ribavirin, BMS200,475, vidarabine or ARA-AMP.Preferred nucleoside analog comprises penciclovir, famciclovir and lamivudine.
Another kind of possible antiviral agent is an interferon.It preferably then is alpha-interferon.
Structure and active knowledge about nucleoside analog can obtain in the bibliography by pharmacy industry authority, for example by PJB publications Limited, Richmond, Surrey, U.K. Fa Hang " Pharmarojects " or IMS World publications, 364Euston Road, London Nw1 3BL distribution " R﹠amp; D Focus ".
When mentioning the anti-hepatitis B virus nucleoside analog, comprise such as hydrate equal solvent compound and specific compound mentioned above and salt thereof.
The example of the salt that pharmacy is allowed referenced patent and the list of references wherein quoted of Beecham Group p.l.c. as mentioned is described, and its subject matter all is hereby incorporated by.
Will be appreciated that, anti-hepatitis B virus nucleoside analog of the present invention or nucleotide analog and HBV vaccine can with other forms of pharmacologically active agents, particularly other antiviral agent, combination medicine-feeding.
The vaccine that is used for preventing and/or treating hepatitis B infection among the present invention comprises all vaccines and the treatment vaccine that contains HBV antigen (as surface antigen, core and polymerase).
As a kind of form of the present invention, hepatitis B virus antigen is hbs antigen (HbsAg).The preparation method of hbs antigen has description in the literature.For example can be with reference to Harford et.al., Develop.Biol.Standard 54,125 (1983), Gregg et.al.Biotechnology, 5,479 (1987), EP-A-0226846, EP-A-0299108 and list of references wherein.
" hbs antigen " in the literary composition or " HBsAg " comprise all HBsAg antigens or its immunogenic derivatives, and particularly it demonstrates the antigenic fragment of HBV surface antigen.It should be understood that, except 226 amino acid whose HBsAg S antigen sequences (are seen Tiollaiset.al.Nature, 317,489 (1985) and list of references) outside, HBsAg described in the literary composition also can under the situation of needs, contain above list of references and EP-A-0278940 described before all or part of of S sequence.HBsAg described in the literary composition also can refer to variant, as WO91/14703 described " escape mutant ".As another kind of form, HBsAg can contain just like a kind of albumen that is described as L* in the European Patent Application No. 04414374, this proteic aminoacid sequence is made up of the partial amino-acid series of big (L) albumen (ad or ay hypotype) of hepatitis B virus, it is characterized in that this proteic aminoacid sequence by:
(1) the proteic 12-52 of described L position residue is 133-145 position residue then, is 175-400 position residue then; Or
(2) proteic the 12nd residue of described L is 14-52 position residue then, is 133-145 position residue then, is that 175-400 position residue is formed then.
HBsAg also can refer to the described polypeptide of EP0198474 or EP0304578.
HBsAg is generally particle form.It can contain S albumen separately, also can be used as composite particles, as (S, L*), wherein the definition of L* as above, S then represents the S-albumen of hbs antigen.
Preferred hepatitis B antigen is this composite particles, is expressed as S, L*.
HBV surface antigen 226 aminoacid sequences that another preferred hepatitis B antigen is a particle form.
Consider for convenience, can contain the excipient that a kind of pharmacy is allowed in the vaccine, as suitable adjuvant.Suitable adjuvant comprises aluminum salt; as gel aluminum hydroxide (Alumen) or aluminum phosphate (as described in WO93/24148); also can be calcium salt, iron salt or zinc salt, or the insoluble suspension of acidylate tyrosine, acidylate sugar, polysaccharide cationic derivative or anionic derivative or polyphosphazene.
Consider that for convenience hepatitis B virus can be prepared with strong adjuvant system.Thus, in compound method of the present invention, preferably used adjuvant system can be induced the immunne response that comprises that TH1 replys.Suitable adjuvant system comprises, for example, monophosphoryl lipid A, preferably 3-takes off-O-acidylate monophosphoryl lipid A (3D-MPL), uses with a kind of aluminum salt binding.Contain hbs antigen and in European Patent Application No. 0633784, describe to some extent with the vaccine that 3D-MPL unites use.
The enhancing system relates to monophosphoryl lipid A is used in combination with a kind of saponarin derivant, particularly disclosed QS21 is used in combination with 3D-MPL among the WO94/00153, thereby or the disclosed cholesterol cancellation QS21 that uses obtains than low reaction originality compositions among the WO96/33739.
Addible other known adjuvant comprises that the CpG that contains oligonucleotide (sees Universityof Iowa; WO9602555).
A kind of HBV of containing antigen is provided in a preferred embodiment of the present invention and is the vaccine of adjuvant with monophosphoryl lipid A or derivatives thereof.
Preferred vaccine contains a kind of saponarin, the preferred QS21 that then contains in addition.
Preferred dosage form contains a kind of oil-in-water emulsion and tocopherol in addition.
WO95/17210 has described a kind of especially effectively adjuvant prescription that contains QS21,3D-MPL and tocopherol in oil-in-water emulsion.
The present invention also provides a kind of hepatitis b virus infected method that treats and/or prevents, this method comprise with safe and effective dosage 1) have an active antiviral agent of resistance of hepatitis B and 2) and the vaccine that is used for preventing and/or treating hepatitis B infection simultaneously or with random order successively to suffering from or easily suffering from hepatitis b virus infected human or animal's main body administration.
The form cooperativing medicine-feeding that salt of allowing such as antiviral agent such as penciclovir/famciclovir and HBV vaccine or pharmacy or ester can adopt two drug alone compositions that use simultaneously or use successively.When individually dosed, these active component generally can carry out administration according to routine dose and dosage regimen thereof.Initial administration (commencement of administration) can be used vaccine, also can use antiviral agent.
The present invention also provides the application of antiviral compound in drug manufacture, and this medicine is used for by hepatitis B vaccine sensitization and suffers from hepatitis b virus infected patient's treatment.The present invention also provides the application of hepatitis B vaccine in drug manufacture, and this medicine is used for by antiviral complex sensitization and suffers from hepatitis b virus infected patient's treatment.Preferred antiviral agent is a nucleoside analog, and most preferred is penciclovir/famciclovir or lamivudine.Preferred hepatitis B vaccine is as indicated above.
The administration unit dose of nucleoside analog or nucleotide analog can be, for example, and every day 1-4 time.Concrete dosage then depends on the degree that is in a bad way of route of administration and treatment, should be appreciated that simultaneously, and this dosage needs according to the different of patient age and body weight conventional change is arranged, and need improve dosage to the patient of non-responsiveness.
Vaccine is to carry out multiple dose administration with different intervals.Generally be per two week or every month administration 6-12 agent.
When adopting simultaneously administering mode, preferably the composition in the medicated bag is provided with independent dosage form, as be used for vaccine form that two arms are inoculated respectively.But also can consider before administration, each composition to be mixed, then administration simultaneously.These compositions can adopt the enteral administering mode, as oral, also can adopt the parenteral mode (as intramuscular or, more particularly, intravenous administration).
Antiviral agent of the present invention can utilize conventional method to be formulated into tablet.Be used for oral compositions, as tablet or capsule, the preparation excipient that can use pharmacy to allow according to conventional methods, as binding agent (as gelatinize corn starch, polyvinylpyrrolidone or hydroxypropyl emthylcellulose); Filler (as lactose, microcrystalline Cellulose or calcium hydrogen phosphate); Lubricant (as magnesium stearate, Pulvis Talci or Silicon stone); Disintegrating agent (as potato starch or sodium starch glycollate); Or wetting agent (as sodium lauryl sulphate).Also can utilize the known method in this field that tablet is carried out coating.The fluid preparation that is used for oral administration can adopt, for example, the form of solution, syrup or suspension, also can be used as drying agent provides, and is reconstructed with water or other suitable carrier before use.The additive that the preparation of these fluid preparations can use pharmacy to allow according to conventional methods is as suspending agent (as sorbitol syrups, cellulose derivative or hydrogenation edible fat); Emulsifying agent (as lecithin or arabic gum); Non-aqueous carrier (as almond oil, grease, ethanol or fractionated vegetable oil); And antiseptic (as methyl parahydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid).Said preparation also can suitably contain buffer salt, flavoring agent, coloring agent and sweeting agent under the situation.
The preparation that is used for oral administration can be realized the controlled release of one or both active component through suitably preparing.
The compositions that is used for parenteral can adopt and be suitable for the bolus injection injection or continue dabbling form.The preparation that is used to inject can adopt the unit dosage form that is added with antiseptic to place, and for example, provides in syringe, ampulla or the multi-dose container.
The reactive antiviral agent can be adopted the form of suspension, solution or the emulsion of oiliness or aqueous carrier, and can contain ingredients such as suspending agent, stabilizing agent and/or dispersant.As selection, these active component also can adopt form of powder, and before use with suitable carrier, as pyrogen-free sterilized water, make up.
The reactive antiviral agent that is used for rectally can be mixed with suppository or retention enema forms, for example, contains such as conventional suppository auxiliary agents such as cocoa butter or other glyceride.
Reactive antiviral agent of the present invention can be prepared according to the known routine techniques in this field.Thus can be under the situation of needs with lamivudine/penciclovir/famciclovir with, for example, appropriate excipients is mixed mutually.The preparation of tablet can be adopted, for example, and direct method with the mixture compression.Capsular preparation can use suitable filling machine that mixture and suitable vehicle together are filled in the gelatine capsule.The preparation that is used for the controlled release forms of oral or rectally can adopt the conventional method relevant with controlled release forms to be prepared.
The nucleoside analog of anti-hepatitis B virus can utilize conventional method to be identified, tests as the in vitro study by the primary duck hepatocyte culture that infected by DHB (DHBV).The variation of preS1 and/or viral DNA level shows that then it has activity in the culture that this analog is handled.As selection, analog also can be identified according to its interference performance to the normal acylation of the synthetic peptide of the hepatitis B virus N terminal amino acid that is equivalent to DHBV or people, woodchuck, ground squirrel or other animal.
Embodiment
In the Canis familiaris L. body, carry out hbs antigen vaccine/lamivudine
Pharmacokinetics effect researchMethod
Adopt following vaccine combination.Used HBV surface antigen is except that being the dried frozen aquatic products, and all the other are equal to the Engerix-B vaccine of commercial form
TM(Smithkline BeechamBiologicals) employed antigen.
Freeze-dried antigen:
HBsAg?????????????????????????100μg
Sucrose 12.6mg
NaCl??????????????????????????20.3mM
NaH
2PO
4/Na
2HPO
4?????????1.35mM
Adjuvant system:
Oil-in-water emulsion: 250 μ l
-Squalene 10.7mg
-DL-tocopherol 11.9mg
-polyoxyethylene sorbitol acid anhydride list
Oleate (Tween 80) 4.8mg
Monophosphoryl lipid A 100 μ g
QS21??????????????????????????100μg
Water for injection q.s.ad 0.5ml
Na
2HPO
4????????????????????575μg
KH
2PO
4?????????????????????100μg
KCl???????????????????????????100μg
NaCl??????????????????????????4mg
pH????????????????????????????6.8+/-0.2
Every day with the oral capsule form with lamivudine (Zeffix
TM, GlaxoWellcome) to three male dogs and three female Canis familiaris L. administrations, dosage is every every 100mg of Canis familiaris L., continues for 6 weeks.14th, 28 and 42 days the time before the lamivudine administration in the intramuscular injection mode with the instant administration of above-mentioned HBs/ Adjuvanted vaccines.7th, 14,28 and 42 days the time before the lamivudine administration and administration blood sampling after 0.5,0.75,1,2,4,6,8,12 and 24 hour.Isolating blood plasma is tasked at branch and is frozen in-20 ℃ before Pharma Bio-Research carries out the analysis of lamivudine plasma concentration.
Collect serum on the 0th, 29 and 43, be used for anti-HBs antibody evaluation.The result
The lamivudine pharmacokinetics
Blood sampling on the the 7th, 14,28 and 42 at 6 all toxicity research, be used for male and female Canis familiaris L. systemic exposure is estimated in lamivudine, every Canis familiaris L. every day by 100mg/ only/day dosage carry out the lamivudine oral administration and the 14th, 28 and 42 day before the lamivudine administration in the intramuscular injection mode with the instant administration of HBs vaccine.Utilize in the Pharma Bio-Research measuring samples 24 hours lamivudine plasma concentration after administration.
The sample of all samplings day all is the maximum mean plasma concentration that occurred lamivudine after administration in 2 hours, has only female Canis familiaris L. in the 7th day sampling exception, and the maximum mean plasma concentration of its lamivudine appears at after the administration 1 hour.The maximum mean plasma concentration of the lamivudine of sampling on the 28th is lower than the numerical value of sampling on the the 7th, 14 and 42.After reaching maximum, the maximum mean plasma concentration of lamivudine reduces with the speed of approximate twice power (apparentlybiexponential).
Below be that sampling sample on the the 7th, 14,28 and 42 is evaluated 24 hours the maximum mean plasma concentration (Cmax) of lamivudine and the bottom area (AUC of lamivudine plasma concentration-time graph to the administration
24) summary, be standard deviation in the bracket:
Cmax(ng/ml)
| The 7th day | The 14th day | The 28th day | The 42nd day | ||||
| Male | Female | Male | Female | Male | Female | Male | Female |
| ??3045 | ??4290 | ??3176 | ??3555 | ??2053 | ??2542 | ??3277 | ??3287 |
| ??(1516) | ??(3335) | ??(871) | ??(1901) | ??(515) | ??(1255) | ??(567) | ??(1256) |
AUC
24(ng.h/ml)
| The 7th day | The 14th day | The 28th day | The 42nd day | ||||
| Male | Female | Male | Female | Male | Female | Male | Female |
| ??12541 | ??11514 | ??12858 | ??13567 | ??11629 | ??8883 | ??12585 | ??11049 |
| ??(2211) | ??(4324) | ??(3231) | ??(5957) | ??(2694) | ??(2534) | ??(1182) | ??(4334) |
As if the time that maximal plasma concentration (Tmax) appears in different Canis familiaris L.s generally all is 2 hours, and excursion is 0.75-4 hour, and does not rely on the administration of HBs vaccine.
The the 71st and No. 73 buck and No. 70 jenny all can measure in the lamivudine plasma concentration of all time points of the 7th, 14,28 and 42 day, so these animals continue to expose (exposure) in the lamivudine of measurable concentration during dosing interval.
Female Canis familiaris L. systemic exposure in the speed (Cmax) of lamivudine a little more than male dog.And female Canis familiaris L. systemic exposure is in the degree (AUC of lamivudine
24) generally a little less than male dog.But there is not tangible statistics evidence to show that there is any gender-related difference (p 〉=0.57) in systemic exposure.
The Canis familiaris L. systemic exposure is in the 14th, 28 and 42 day speed (Cmax) and degree (AUC of lamivudine
24) general similar to the 7th day value, but as if female Canis familiaris L. be lower than the 7th day value at the 14,28 and 42 day cmax value.Generally speaking, there is not tangible statistics evidence to show that there is any difference relevant with the time (p 〉=0.08) in the speed of systemic exposure with degree.Below be based on AUC
24The accumulating rate meansigma methods of value:
| Accumulating rate | ||
| Male | Female | |
| The 14th day/the 7th day | ????1.0 | ????1.2 |
| The 28th day/the 7th day | ????0.9 | ????0.8 |
| The 42nd day/the 7th day | ????1.0 | ????1.0 |
Average accumulating rate is generally approaching or less than 1, this shows the accumulation that does not have or seldom occur lamivudine behind the HBs vaccine administration.
Table 5-8 provides the 7th, 14,28 and 42 day final speed constant of lamivudine and corresponding final half life.Computable final speed constant is 0.32 39-0.1364/ hour, and the final half life that is equivalent to lamivudine is 2.1-5.1 hour.
SerologyMethod
Utilize ELISA method HBs (Hep286) to carry out quantitatively for envelope antigen antagonism HBs antibody.Antigen and the antibody-solutions that use in every hole are 100 μ l.With PBS with antigen diluent to final concentration 1 μ g/ml, and (MaxisorbImmuno-plate, Nunc is in hole Denmark) to be adsorbed in 96 hole microtitration plates under 4 ℃ of conditions of spending the night.With the PBS that contains 5% defatted milk powder and 0.1%Tween20 plate is incubated 1.5 hours down at 37 ℃ then.With the dilution of serum twice successively (since 1/50 or 1/200 dilution factor) and be added in the plate of HBs bag quilt, 37 ℃ are incubated 1 hour with the PBS that contains 0.5%Gloria milk and 0.1%Tween20.(Rockl and, USA), insulation is 1 hour under the room temperature in the anti-Canis familiaris L. IgG of the HRPO coupling of 0.5% defatted milk powder and 0.1%Tween20 buffer with 1/40000 dilution proportion for the adding of every hole.Implement cleaning step, (Biorad, USA) solution is incubated 10 minutes with plate under room temperature with 2 times of tetramethyl benzidines (TMB) that are diluted in citrate buffer (0.1M pH=5.8) then.Use 0.5N H
2SO
4Cessation reaction also places reading under the 450/630nm with plate.ELISA tires and tires for mid point.The result
Utilized ELISA antagonism HBs seroreaction to measure in the 0th, 29 and 43 day.Following table provides mid point and tires:
The mid point of anti-HBs antibody is tired
| The Canis familiaris L. numbering | The 0th day | The 29th day | The 43rd day |
| ????69 | ?????25 | ????679 | ????7258 |
| ????71 | ?????25 | ????389 | ????3780 |
| ????73 | ?????25 | ????705 | ????6496 |
| ????70 | ?????25 | ????63 | ????1027 |
| ????72 | ?????25 | ????176 | ????3821 |
| ????74 | ?????25 | ????582 | ????11482 |
| On average | ?????25 | ????383 | ????5321 |
The 0th day mid point tire meansigma methods be 25 (optional is first dilution 1/2), the 29th day be 383, the 43 days be 5321.This clearlys show and has induced immunne response.Conclusion
In a word, with 100mg/ only/day dosage lamivudine is carried out repeatedly oral administration after, as if the Canis familiaris L. systemic exposure do not rely in 6 all pharmacokinetics effects researchs the 14th, 28 and 42 day HBs vaccine administration in the speed of lamivudine and degree.Do not have evidence to show and exist systemic exposure between male dog and the female Canis familiaris L. in the speed of lamivudine and the difference of degree.
As if the pharmaccine administration can be caused immunity and induce the anti-HBs antibody of high cyclical level, illustrate that the Beagle Canis familiaris L. can be used for the research of this type of PK effect.
Claims (19)
1. a medicated bag wherein comprises antiviral agent and (2) a kind of vaccine that is used for preventing and/or treating hepatitis B infection that active component (1) has anti-hepatitis B virus activity, and this active component can use simultaneously or successively.
2. the medicated bag of claim 1 is used for the treatment of hepatitis B infection.
3. the medicated bag of claim 1 is used for the prevention of hepatitis B infection.
4. the medicated bag of one of above claim, antiviral agent wherein is a kind of nucleoside analog.
5. the medicated bag of claim 4, wherein antiviral agent is selected from penciclovir, famciclovir or lamivudine.
6. the medicated bag of one of claim 1-3, antiviral agent wherein is a kind of nucleotide analog.
7. claim 4 or 6 medicated bag, wherein antiviral agent is selected from ganciclovir, lobucavir, adefovir, ribavirin, BMS200,475, vidarabine or ARA-AMP.
8. the medicated bag of one of claim 1-3, antiviral agent wherein is an alpha-interferon.
9. the medicated bag of one of above claim wherein has the active vaccine of resistance of hepatitis B and contains hbs antigen.
10. the medicated bag of claim 9 wherein has the active vaccine of resistance of hepatitis B and contains antigen SL*.
11. the medicated bag of claim 9 wherein has the active vaccine of resistance of hepatitis B and contains 226 amino acid whose S antigens.
12. the medicated bag of one of above claim, vaccine wherein contains a kind of adjuvant.
13. the medicated bag of claim 12, wherein adjuvant is selected from: the adjuvant of the mixture of 3D-MPL, QS21, QS21 and cholesterol, CpG oligonucleotide, aluminium hydroxide, aluminum phosphate, tocopherol or a kind of oil-in-water emulsion, or the compositions of above-mentioned two or more described adjuvants.
14. the medicated bag of claim 13, adjuvant wherein contain 3D-MPL, QS21 and a kind of oil-in-water emulsion.
15. the medicated bag of claim 14, oil-in-water emulsion wherein comprise Squalene, tocopherol and Tween-81 (Tween 80).
16. method, be used to suffer from or easily suffer from hepatitis b virus infected patient's treatment, this method comprise with safe and effective dosage 1) have an antiviral agent and 2 of anti-hepatitis B virus activity) and the vaccine that is used for preventing and/or treating hepatitis B infection simultaneously or with random order successively to patient's administration of this treatment of needs.
17. the method for claim 13, this method comprise the medicated bag that uses one of claim 1-15.
18. antiviral compound is used for treating by hepatitis B vaccine sensitization and suffers from application in hepatitis b virus infected patient's the medicine in production.
19. hepatitis B vaccine is used for treating by antiviral complex sensitization and suffers from application in hepatitis b virus infected patient's the medicine in production.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9900630.6 | 1999-01-12 | ||
| GB9900630 | 1999-01-12 |
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| CN1391482A true CN1391482A (en) | 2003-01-15 |
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Family Applications (1)
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| CN99816471A Pending CN1391482A (en) | 1999-01-12 | 1999-12-21 | Therapy |
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| EP (1) | EP1140163A2 (en) |
| JP (1) | JP2002534438A (en) |
| KR (1) | KR20010090011A (en) |
| CN (1) | CN1391482A (en) |
| AR (1) | AR022250A1 (en) |
| AU (1) | AU760574B2 (en) |
| BR (1) | BR9916893A (en) |
| CA (1) | CA2359110A1 (en) |
| CO (1) | CO5241355A1 (en) |
| CZ (1) | CZ20012544A3 (en) |
| HK (1) | HK1041434A1 (en) |
| HU (1) | HUP0105070A2 (en) |
| IL (1) | IL144186A0 (en) |
| NO (1) | NO20013337L (en) |
| NZ (1) | NZ512890A (en) |
| PL (1) | PL349347A1 (en) |
| TR (1) | TR200102024T2 (en) |
| WO (1) | WO2000041463A2 (en) |
| ZA (1) | ZA200105690B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100443117C (en) * | 2003-05-13 | 2008-12-17 | 深圳康泰生物制品股份有限公司 | Hepatitis B treating vaccine prepn and its prepn process and use |
| WO2020134682A1 (en) * | 2018-12-24 | 2020-07-02 | 南京远大赛威信生物医药有限公司 | Pharmaceutical preparation for treating hepatitis b, preparation method therefor and use thereof |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1733735B1 (en) | 1998-05-22 | 2017-03-22 | Ottawa Hospital Research Institute | Methods and products for inducing mucosal immunity |
| CA2337743C (en) | 1998-07-31 | 2015-07-07 | Yoshihiro Oka | Tumor antigen based on products of the tumor suppressor gene wt1 |
| ES2298353T3 (en) | 2001-03-22 | 2008-05-16 | International Institute Of Cancer Immunology, Inc. | MODIFIED WT1 PEPTIDE. |
| EP1447092A4 (en) * | 2001-09-28 | 2007-07-11 | Haruo Sugiyama | Methods of inducing antigen-specific t cells |
| US8735357B2 (en) | 2001-09-28 | 2014-05-27 | International Institute Of Cancer Immunology, Inc. | Method of inducing antigen-specific T cells |
| TWI275392B (en) * | 2002-04-08 | 2007-03-11 | Bristol Myers Squibb Co | Low dose liquid entecavir formulations and use |
| ZA200503511B (en) | 2002-10-29 | 2006-10-25 | Coley Pharmaceutical Group Ltd | Use of CPG oligonucleotides in the treatment of hepatitis C virus infection |
| US7956043B2 (en) | 2002-12-11 | 2011-06-07 | Coley Pharmaceutical Group, Inc. | 5′ CpG nucleic acids and methods of use |
| US8541167B2 (en) | 2004-06-03 | 2013-09-24 | Saint Louis University | Methods and compositions for vaccination |
| WO2008104133A1 (en) * | 2007-02-28 | 2008-09-04 | Centro De Ingeniería Genética Y Biotecnología | Combination therapy for the treatment of chronic hepatitis b |
| CN117120088A (en) * | 2021-04-07 | 2023-11-24 | 电化株式会社 | Adjuvant activity enhancer and adjuvant composition |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0414374B1 (en) * | 1989-07-25 | 1997-10-08 | Smithkline Biologicals S.A. | Novel antigens and methods for their preparation |
| BR9908599A (en) * | 1998-03-09 | 2000-11-14 | Smithkline Beecham Biolog | Combined vaccine compositions |
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1999
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- 1999-12-21 EP EP99965531A patent/EP1140163A2/en not_active Withdrawn
- 1999-12-21 KR KR1020017008833A patent/KR20010090011A/en not_active Application Discontinuation
- 1999-12-21 AU AU21009/00A patent/AU760574B2/en not_active Ceased
- 1999-12-21 TR TR2001/02024T patent/TR200102024T2/en unknown
- 1999-12-21 BR BR9916893-6A patent/BR9916893A/en not_active IP Right Cessation
- 1999-12-21 PL PL99349347A patent/PL349347A1/en not_active Application Discontinuation
- 1999-12-21 CA CA002359110A patent/CA2359110A1/en not_active Abandoned
- 1999-12-21 CN CN99816471A patent/CN1391482A/en active Pending
- 1999-12-21 IL IL14418699A patent/IL144186A0/en unknown
- 1999-12-21 HU HU0105070A patent/HUP0105070A2/en unknown
- 1999-12-21 JP JP2000593088A patent/JP2002534438A/en active Pending
- 1999-12-21 NZ NZ512890A patent/NZ512890A/en unknown
- 1999-12-21 WO PCT/EP1999/010295 patent/WO2000041463A2/en not_active Application Discontinuation
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2000
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2001
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2002
- 2002-02-19 HK HK02101211.9A patent/HK1041434A1/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100443117C (en) * | 2003-05-13 | 2008-12-17 | 深圳康泰生物制品股份有限公司 | Hepatitis B treating vaccine prepn and its prepn process and use |
| WO2020134682A1 (en) * | 2018-12-24 | 2020-07-02 | 南京远大赛威信生物医药有限公司 | Pharmaceutical preparation for treating hepatitis b, preparation method therefor and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9916893A (en) | 2001-11-20 |
| CO5241355A1 (en) | 2003-01-31 |
| CZ20012544A3 (en) | 2002-01-16 |
| WO2000041463A3 (en) | 2000-11-09 |
| NZ512890A (en) | 2003-09-26 |
| AR022250A1 (en) | 2002-09-04 |
| NO20013337L (en) | 2001-08-17 |
| KR20010090011A (en) | 2001-10-17 |
| CA2359110A1 (en) | 2000-07-20 |
| AU2100900A (en) | 2000-08-01 |
| AU760574B2 (en) | 2003-05-15 |
| WO2000041463A2 (en) | 2000-07-20 |
| IL144186A0 (en) | 2002-05-23 |
| EP1140163A2 (en) | 2001-10-10 |
| ZA200105690B (en) | 2002-09-25 |
| PL349347A1 (en) | 2002-07-15 |
| JP2002534438A (en) | 2002-10-15 |
| HK1041434A1 (en) | 2002-07-12 |
| TR200102024T2 (en) | 2001-12-21 |
| NO20013337D0 (en) | 2001-07-05 |
| HUP0105070A2 (en) | 2002-04-29 |
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