CN1401389A - Hepatitis B vaccine preparation - Google Patents
Hepatitis B vaccine preparation Download PDFInfo
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- CN1401389A CN1401389A CN 02146247 CN02146247A CN1401389A CN 1401389 A CN1401389 A CN 1401389A CN 02146247 CN02146247 CN 02146247 CN 02146247 A CN02146247 A CN 02146247A CN 1401389 A CN1401389 A CN 1401389A
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Abstract
A novel hepatitis B vaccine contains the genetically engineered surface antigen of hepatitis B virus, human surface antigen antibody of heptitis B, Al adjuvant and A(MPL). Its advantage is high immunogenicity.
Description
Technical field:
The present invention relates to a kind of new bacterin preparation, particularly hepatitis B vaccine preparation, the prescription that said preparation adopts can induce body to produce stronger immunoreation.Can be used for being grown up, other type hepatitis b vaccination loser, kidney dialysis patient, organ transplantation patient's immunity, and the immunization therapy of chronic hepatitis B patients.
Background technology:
Hepatitis B virus (HBV) is a hepadnavirus, has double-shell structure, shell contains hbs antigen (HBsAg), pre-s1 protein (PreS1) and pre-s2 protein (PreS2), the surface of kernel is hepatitis B core antigen (HBcAg) and e antigen (HBeAg), and kernel includes double-stranded cyclic DNA and DNA polymerase (DNA-P).
After China in 1985 carried out hepatitis B vaccine inoculation work, the hepatitis B virus carrier rate was reduced to about 1% about by 10% in immune child.Ground such as Beijing, Shanghai is owing to neonate hepatitis B vaccine rate of vaccination height, and the hepatitis B virus carrier rate of preschooler is reduced to below 0.5%.Facts have proved that as other vaccine preventable disease, inoculating hepatitis B vaccine and uniting the use hepatitis B immune globulin is prevention and the most effective weapon of control hepatitis B.The inoculation hepatitis B vaccine not only can prevent hepatitis B, and can prevent the hepatocarcinoma relevant with hepatitis B virus, can also prevent hepatitis D simultaneously.
At present the every dosage of hepatitis B vaccine that uses of China contains the HBsAg of the HBsAg of 5 μ g, 10 μ g yeast expressions or 10 μ g, 20 μ gCHO cellular expressions, and every dosage contains 0.5～1.0mg aluminium adjuvant.The vaccine dose that is used for organ transplantation, kidney dialysis and immunocompromised person that USA MSD Co. is produced is 40 μ g/ agent.
Used hepatitis B vaccine is the vaccine of aluminium hydroxide adjuvant, can induce humoral immunization preferably, but is difficult to bring out high-caliber humoral immunization.The present invention joins detoxification monophogphoryl lipid A (MPL) in the vaccine that contains HBsAg, people's anti-HBs antibody (HBIG) and aluminium adjuvant, can effectively stimulate body to produce high-level humoral immunization.
The therapeutic hepatitis B vaccine of shanghai Medicine institute of Fudan University development contains hbs antigen and HBIG (hbs antigen excess), before clinical, show effect in zoopery and the limited clinical practice, in animal experiment, also shown the effect of irritation cell immunity with good lifting human body humoral immunization.The present invention and its difference are the amount equalizations of antigen and antibody, and the no more than antibody of promptly antigenic addition has also added immunostimulant MPL in addition, and zooperal result obviously is better than used Hepatitis B virus vaccine.The humoral immunization and the cellular immunization of the raising human body anti-hepatitis B virus of spoke degree can be used for the treatment of chronic hepatitis B patients greatly.
Summary of the invention:
The invention provides a kind of new hepatitis B vaccine preparation, said preparation is characterised in that, in prescription, added nontoxic (detoxification) monophogphoryl lipid A (being designated hereinafter simply as MPL), and the amount equalization of antigen and antibody, be the no more than antibody of antigenic addition, hepatitis B vaccine of the present invention is based on to be broken immune system cell and designs to HBV virus immunity tolerance or to HBsAg low reaction person, the Fc receptors bind on people's antibody Fc section that vaccine is contained and antigen-presenting cell (APC) surface, initiatively present hepatitis B virus surface antigen, under the situation that MPL exists, activated T cell effectively, can produce stronger humoral immunization, in the test Mus, induce high-caliber resisting-HBs.Adopt the angtigen presentation of novel immunostimulant of this kind and particular type both can carry out effective immunity to the immunosuppressive drug user, can carry out immunization therapy to the chronic HBV infection person again, be expected to more refractory asymptomatic HBV surface antigen (HBsAg) carrier is at present turned out cloudy and occurred resisting-HBs.Existingly studies have shown that in the vaccine that adding MPL can induce body to produce high-caliber specific humoral immunity and cellular immunization, what contain MPL is that the Hepatitis B virus vaccine of main component bring bright prospect will for the treatment of chronic hepatitis B with hepatitis B virus surface antigen etc.
The hbs antigen of using among the present invention is the genetic engineering recombinant antigen, rather than derives from the hbs antigen of hepatitis B human plasma.Genetic engineering surface antigen by yeast or expressing cho cell is made up of 226 aminoacid.The HBsAg of recombinant yeast or expressing cho cell all can form the 22nm granule, has been used for surplus the community immunity ten year, all shows the hepatitis b virus infected effect of good preventing.Employed nontoxic (detoxification) MPL is available from U.S. Avanti Polar Lipids in the hepatitis B vaccine prescription of the present invention, and Inc, many reports show that MPL can effectively improve humoral immunization and cellular immunization, has been widely used in the prescription of novel protein class vaccine.
Hepatitis B vaccine preparation of the present invention contains hepatitis B virus surface antigen, MPL, HBIG, aluminium adjuvant, hbs antigen or its fragment that hbs antigen wherein can be expressed for recombination yeast manufacturing or recombinant C HO or the antigen that contains pre S1/Pre S2 composition.
Bacterin preparation of the present invention, wherein, HBIG can be the people anti--HBs, humanization be anti--HBs monoclonal antibody or humanized be anti--the HBs monoclonal antibody.
Bacterin preparation of the present invention, but human body or microprotein and the polysaccharide or the micromolecular compound of other known human body immunity improving also can be contained.
The content range of each main constituent is as follows in every dose of the preferred bacterin preparation of the present invention: MPL 10～100 μ g, HBsAg 5～120 μ g, HBIG 5～100IU, aluminium ion 0.25～1.20mg.
The present invention comprises also that bacterin preparation of the present invention is used for being grown up in preparation, the application of the medicine of kidney dialysis patient, organ transplantation patient and hepatitis B high-risk group immunity.And the application in the immunotherapy medicaments of preparation chronic hepatitis B patients.
Bacterin preparation of the present invention can adopt following method preparation:
With water dissolution detoxification MPL, with phosphate buffer dissolving genetic engineering hbs antigen, with certain amount of H BsAg and not commensurability HBIG reaction, use HBsAg remaining in the EIA kit measurement reaction system and the amount of HBIG then, determine to make the antigen more than 95% and antibody in the reaction system all to participate in the antibody amount of reacting.Add aluminium adjuvant in quantitative HBsAg solution, room temperature condition is placed down, adds HBIG (also can add) in predetermined ratio before adding aluminium adjuvant, and room temperature condition reacts down, adds the MPL solution of debita spissitudo again.According to the addition of HBsAg, adjust the cumulative volume of suspension with phosphate buffer, add 1% thimerosal (also can not adding) more promptly.
Animal experiment shows that novel hepatitis B vaccine of the present invention is safe, and experimental animal is not had visible toxicity.Can effectively stimulate animal to produce the specific antibody of high titre.
The hepatitis B vaccine that is equipped with by above-mentioned compound method and the hepatitis B vaccine or the immunological testing of control vaccine in mice of other formulated are summarized as follows:
Material: genetic engineering (yeast) hbs antigen (20 μ g/ml), anti--HBs Mab (3.0mg/ml), murine antibody (Mab, 3.0mg/ml), aluminum hydroxide adjuvant (1.0mg/ml), aluminum phosphate adjuvant (1.0mg/ml), MPL (2.0mg/ml), normal saline.
Equipment: Labsystem MK3 microplate reader, refrigerator, 37 ℃ of incubators, wash plate machine, analytical balance, adjustable quantitative pipettor, glass pipette.
Test method: earlier 5mg MPL is dissolved in the 2.5ml normal saline, ultrasonic Treatment 1 minute, standby.The dosage of each test group adjuvant and various compositions sees Table 1:
The preparation group HBsAg Al (OH) of table 1, different adjuvant hepatitis B vaccines
3AlPO
4MPL Anti-HBs Mab Mab HBIG normal saline closes
(20 μ g/ml) (1.0mg/ml) (1.0mg/ml) (2mg/ml) (3mg/ml) (3mg/ml) (270IU/ml) meter
ml????????????ml??????????ml?????????μl?????????????μl?????????μl???????μl??????????ml???????mlH1???????????4.0???????????4.0?????????/???????????/???????????????/???????????/??????????/??????????/????????8.0H2???????????4.0???????????4.0?????????/???????????/???????????????14.0????????/??????????/??????????/????????8.0H3???????????4.0???????????4.0?????????/???????????40.0????????????14.0????????/??????????/??????????/????????8.0H4???????????4.0???????????4.0?????????/???????????40.0????????????/???????????14.0???????/??????????/????????8.0H5???????????4.0???????????4.0?????????/???????????40.0????????????/???????????/??????????100????????/????????8.1H6???????????4.0
*?????????4.0?????????/???????????/???????????????7.0?????????/??????????/??????????/????????8.0P6???????????4.0???????????/???????????4.0?????????/???????????????/???????????/??????????/??????????/????????8.0P7???????????4.0???????????/???????????4.0?????????/???????????????7.0?????????/??????????/??????????/????????8.0P8???????????4.0???????????/???????????4.0?????????40.0????????????14.0????????/??????????/??????????/????????8.0P9???????????4.0???????????/???????????4.0?????????40.0????????????/???????????14.0???????/??????????/????????8.0P10??????????4.0???????????/???????????4.0?????????40.0????????????/???????????/??????????100????????/????????8.1N????????????0.0???????????/???????????/???????????40.0????????????/???????????/??????????/??????????8.0??????8.0
* earlier 2.0ml is contained solution and the anti-HBs Mab reaction of HBsAg, add the solution 2.0ml that 2.0ml contains HBsAg after 24 hours again.
Get 120 of the female BALB/C mice of SPF level, be divided into 12 groups, every group of 10 mices are indicated group respectively.Each organizes mice other vaccine of lumbar injection respective sets 0.10ml respectively.After 28 days, with same kind, immune once more with the vaccine of dosage.Heart blood sampling after 7 days behind the separation of serum, is measured the content of anti--HBs in the serum with dual-antigen sandwich method EIA hepatitis B surface antibody detectable (Beijing Tso Biological Pharmaceutical Co).The HBIG standard substance of providing with Nat'l Pharmaceutical ﹠ Biological Products Control Institute (World Health Organization (WHO)) during detection are done contrast, calculate the relative amount (IU/ml) of antibody in the serum.The results are shown in Table 2
The hepatitis B vaccine of table 2, different formulations induces the comparison of antibody in mice
* each laboratory animal serum anti-HBs detection by quantitative result is all negative, does not calculate mean and standard deviation.
| Group | Constituent | BALB/C mice number of elements | Serum resists-HBs titre (IU/ml) | |
| ?????GMT | ????SD | |||
| ?H1 | ?HBsAg，Al(OH) 3， | ????10 | ????14.05 | ????11.34 |
| ?H2 | ?HBsAg，Al(OH) 3，Anti-HBs?Mab | ????10 | ????67.02 | ????4.15 |
| ?H3 | ?HBsAg，Al(OH) 3，MPL，anti-HBs?Mab | ????10 | ????149.49 | ????12.55 |
| ?H4 | ?HBsAg，Al(OH) 3，MPL，Mab | ????10 | ????13.17 | ????8.21 |
| ?H5 | ?HBsAg，Al(OH) 3，MPL，HBIG | ????10 | ????27.98 | ????2.75 |
| ?H6 | ?HBsAg，Al(OH) 3, Anti-HBs Mab (antibody amount be H2 group 1/2) | ????10 | ????72.62 | ????12.36 |
| ?P6 | ?HBsAg，AlPO 4， | ????10 | ????52.58 | ????7.95 |
| ?P7 | ?HBsAg，AlPO 4，Anti-HBs?Mab | ????10 | ????261.45 | ????3.51 |
| ?P8 | ?HBsAg，AlPO 4，MPL，anti-HBs?Mab | ????10 | ????504.31 | ????2.21 |
| ?P9 | ?HBsAg，AlPO 4，MPL，Mab | ????10 | ????118.45 | ????3.77 |
| ?P10 | ?HBsAg，A1PO 4，MPL，HBIG | ????10 | ????64.44 | ????3.88 |
| ?N | Normal saline | ????10 | ????＜0.010 * | ????- |
As can be seen from the above table, the vaccine of adding anti-HBs Mab and MPL group induces tiring apparently higher than other group of Anti-HBs; The immune effect of aluminum phosphate adjuvant group is better than the aluminium hydroxide group, adds non-hepatitis B surface antigen murine antibody or non-antibody of the same race (HBIG, Human Hepatitis B Immune Globulin) can not obviously increase antibody titer.
Can infer thus, when preparation human hepatitis B vaccine,, prepare the vaccine immunity people, also can obtain similar result with the method in one of example, two, three, four, five as replace Mus anti-HBs Mab with HBIG.
The specific embodiment:
Further specify the present invention by the following examples.
One of embodiment one hepatitis B vaccine preparation method
The detoxification monophogphoryl lipid A is available from U.S. Avanti Polar Lipids, and Inc, hepatitis B virus surface antigen (vaccine) be available from Beijing Biological Product Inst., and the people is anti--and HBs immunoglobulin (HBIG) is available from Shanghai Vaccine and Serum Institute.Aluminium hydroxide, aluminum phosphate adjuvant are our company's self-control product.
MPL is 1.0mg/ml to final concentration with water for injection dissolving detoxification, ultrasound wave hydrotropy (2-20 ℃ of control temperature).
Adjusting genetic engineering hbs antigen (HBsAg) to final concentration with phosphate buffer is 100 μ g/ml.With 1 μ g HBsAg and not commensurability HBIG reaction, use HBsAg remaining in the EIA kit measurement reaction system and the amount of HBIG then, the result shows that making the antibody amount that the antigen more than 95% and antibody all participate in reacting in the reaction system is 1.08 IU.Promptly the HBsAg of 1 μ g can in and the HBIG of 1.08IU.
Get HBsAg (content is 100 μ g/ml) solution 10ml, add 10ml aluminium adjuvant (aluminium composition is 1mg/ml), room temperature condition was placed 24 hours down, during shook 1 time (or lasting low velocity stirs) every 1 hour; Add the 4.0ml height HBIG (270IU/ml) that tires in predetermined ratio, fully behind the mixing, room temperature condition reaction 24 hours down, during per hour jolting once leave standstill careful sucking-off upper water solution to the solution layering; Add isopyknic phosphate buffer mixing again, leave standstill to solution secondary clearing again, sucking-off upper solution; Add isopyknic phosphate buffer again, leave standstill, sucking-off upper solution (washing altogether 3 times) to remove the albumen that is not adsorbed to solution secondary clearing again; The volume that adds phosphate buffer adjustment suspension is 19ml, adds MPL solution (1mg/ml) 0.8ml, adds 1% thimerosal (also can not adding) 0.2ml again.Be positioned over 2～10 ℃, or be distributed into 1.0ml/ under the aseptic condition and prop up 2～8 ℃ of preservations.
Two of embodiment two B-mode hepatitis vaccine preparation methoies
The detoxification monophogphoryl lipid A is available from U.S. Avanti Polar Lipids, Inc company, and hepatitis B virus surface antigen (vaccine) is available from Beijing Biological Product Inst., and HBIG is available from Shanghai Vaccine and Serum Institute.Aluminium hydroxide, aluminum phosphate adjuvant are our company's self-control product.
MPL is 1.0mg/ml to final concentration with water for injection dissolving detoxification, the ultrasound wave hydrotropy.
Adjusting genetic engineering hbs antigen (HBsAg) to final concentration with phosphate buffer is 100 μ g/ml.In 10ml HBsAg solution, add 4.0ml HBIG (seeing embodiment one), room temperature condition reaction 24 hours down (or 37 ℃ of reactions rearmounted 2～8 ℃ of reactions in 2 hours 22 hours), during per hour jolting is once; (1mg/ml presses Al to add the 10ml aluminium adjuvant
3+Calculate), room temperature condition was placed 24 hours down, during shook 1～2 time every 1 hour; Leave standstill to the solution layering careful sucking-off upper solution; Add isopyknic phosphate buffer mixing again, leave standstill to solution secondary clearing again, sucking-off upper solution; Twice of repeated washing; Add the phosphate buffer of proper volume, the cumulative volume that makes suspension is 19.0ml, adds 0.8ml MPL solution afterwards, fully behind the mixing, adds 1% thimerosal 0.2ml (also can not adding) again, is positioned over 2～10 ℃.Or be distributed into 1.0ml/ under the aseptic condition and prop up 2～8 ℃ of preservations.
Three of embodiment three hepatitis B vaccine preparation methoies
The detoxification monophogphoryl lipid A is available from U.S. Avanti Polar Lipids, Inc company, and hepatitis B virus surface antigen (vaccine) is available from Beijing Biological Product Inst., and HBIG is available from Shanghai Vaccine and Serum Institute.Aluminium hydroxide, aluminum phosphate adjuvant are our company's self-control product.
MPL is 1.0mg/ml to final concentration with water for injection dissolving detoxification, the ultrasound wave hydrotropy.
Adjusting genetic engineering hbs antigen (HBsAg) to final concentration with phosphate buffer is 200 μ g/ml.Get HBsAg solution 10ml, add 8.5ml HBIG (excessive 6%, see embodiment one) then, room temperature condition reaction 24 hours down, during per hour jolting is once.Add 18%PEG 6000 solution 3.7ml, abandon supernatant after centrifugal, precipitation with 3% PEG 6000 wash, centrifugal 2 times, reuse 6ml phosphate buffer dissolution precipitation, pack into after the dissolving (molecular cut off is 30KD) in the bag filter, dialysis is 24 hours in phosphate buffer, during change liquid 3 times, or, remove PEG6000 with the ultrafilter ultrafiltration of molecular cut off 300KD.The volume of adjusting the HBsAg-HBIG complex after the dialysis adds 10ml aluminium adjuvant (aluminium composition is 1mg/ml) to 7.8ml, adds 2.0ml MPL solution, and room temperature condition was placed 24 hours down, during shook 1 time every 1 hour.The phosphate buffer that adds proper volume is adjusted the cumulative volume of suspension, adds 1% thimerosal (also can not adding) solution 0.2ml.Packing under the aseptic condition, 0.5～1.0ml/ props up, 2～8 ℃ of preservations.
Four of embodiment tetrem type hepatitis vaccine preparation method
The detoxification monophogphoryl lipid A is available from U.S. Avanti Polar Lipids, Inc company, and hepatitis B virus surface antigen (vaccine) is available from Beijing Biological Product Inst., and HBIG is available from Shanghai Vaccine and Serum Institute.Aluminium hydroxide, aluminum phosphate adjuvant are our company's self-control product.
MPL is 1.0mg/ml to final concentration with water for injection dissolving detoxification, the ultrasound wave hydrotropy.
Adjusting genetic engineering hbs antigen (HBsAg) to final concentration with phosphate buffer is 200 μ g/ml.Get HBsAg solution 10ml, add 8.5ml HBIG (excessive slightly, as to see embodiment one) then, down reaction 24 hours of room temperature condition, during per hour jolting is once.With molecular cut off is the ultrafilter membrane ultrafiltration of 300D or 500KD, removes unnecessary HBIG and foreign protein, adjusts volume to 7.8ml.In the HBsAg-HBIG complex solution, add aluminium adjuvant 10ml and (press Al
3+Calculate, 1mg/ml), room temperature condition was placed 24 hours down, during shook 1 time every 1 hour, put 2～10 ℃ then and deposit.Add 2.0ml MPL solution afterwards.Add 1% thimerosal (also can not adding) 0.2ml again.Packing under the aseptic condition, 0.5～1.0ml/ props up, 2～8 ℃ of preservations.
Five of embodiment five hepatitis B vaccine preparation methoies
The detoxification monophogphoryl lipid A is available from U.S. Avanti Polar Lipids, Inc company, and hepatitis B virus surface antigen (vaccine) is available from Beijing Biological Product Inst., and HBIG is available from Shanghai Vaccine and Serum Institute.Aluminium hydroxide, aluminum phosphate adjuvant are our company's self-control product.
MPL is 1.0mg/ml to final concentration with water for injection dissolving detoxification, the ultrasound wave hydrotropy.
Adjusting genetic engineering hbs antigen (HBsAg) to final concentration with phosphate buffer is 200 μ g/ml.Get HBsAg solution 10ml, add 8.0ml HBIG (seeing embodiment one) then, down reaction 24 hours of room temperature condition, during per hour jolting is once.In the HBsAg-HBIG complex solution that forms, add aluminium adjuvant 10ml and (press Al
3+Calculate, 1.5mg/ml), room temperature condition was placed 24 hours down, during shook 1 time every 1 hour, put 2～10 ℃ then and deposit.Add 2.0ml MPL solution afterwards.Add 1% thimerosal (also can not adding) 0.2ml again.Packing under the aseptic condition, 0.5～1.0ml/ props up, 2～8 ℃ of preservations.Six of embodiment six hepatitis B vaccine preparation methoies
The detoxification monophogphoryl lipid A is available from U.S. Avanti Po1ar Lipids, Inc company, and hepatitis B virus surface antigen (vaccine) is available from Beijing Biological Product Inst., and mouse-anti-HBs-MAb is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.Aluminium hydroxide, aluminum phosphate adjuvant are our company's self-control product.
MPL is 2.0mg/ml to final concentration with water for injection dissolving detoxification, the ultrasound wave hydrotropy.
Adjusting genetic engineering hbs antigen (HBsAg) to final concentration with phosphate buffer is 20 μ g/ml, with the HBsAg of 1 μ g and not commensurability mouse-anti-HBs-MAb (3mg/ml) reaction, use HBsAg remaining in the EIA kit measurement reaction system and the amount of mouse-anti-HBs-MAb then, the result shows that making in the reaction system antigen more than 95% and antibody all participate in the reagin amount is 1 μ g.Promptly in this experiment, the HBsAg of 1 μ g can in and mouse-anti-HBs-Mab of 1 μ g.
In 10ml HBsAg solution, add 67 μ l mouse-anti-HBs-MAb, placed 2 hours for 37 ℃, during shook 1 time every 30 minutes; Add the 10ml aluminium adjuvant then and (press Al
3+Calculate, 0.5mg/ml), fully mix, be positioned over 2～10 ℃.Add 0.1ml MPL solution afterwards, add 1% thimerosal (also can not adding) 0.1ml again.Packing under the aseptic condition, 2～8 ℃ of preservations.This kind is that the hepatitis B vaccine of material preparation is only for being used for zoopery with the Mus monoclonal antibody.
This embodiment can be used as with the people source anti--HBs monoclonal antibody, humanization be anti--the HBs monoclonal antibody substitutes the reference that HBIG prepares hepatitis B vaccine of the present invention.
Claims (10)
1, a kind of hepatitis B vaccine preparation is characterized in that, contains hepatitis B virus surface antigen in the said preparation, aluminium adjuvant, nontoxic monophogphoryl lipid A (MPL), people's anti-HBs antibody (HBIG).
2, the bacterin preparation of claim 1 is characterized in that, the content of MPL is 5-100 μ g in every vaccinating agent, and the content of HBIG is 5-100IU, and the content of HBsAg is 5-120 μ g, aluminium adjuvant (calculating with aluminum ions amount) 0.25-1.2mg.
3, the bacterin preparation of claim 1, wherein, hbs antigen is hbs antigen or its fragment of recombination yeast manufacturing or recombinaant CHO cell manufacturing or the antigen that contains pre S1/Pre S2 composition.
4, the bacterin preparation of claim 1, wherein, HBIG can be the people anti--HBs, humanization be anti--HBs monoclonal antibody or humanized be anti--the HBs monoclonal antibody.
5, the preparation method of the bacterin preparation of claim 1 is characterized in that, prepares amount and the HBIG equivalent of used HBsAg in the technology of this vaccine, and the content of free antigen, antibody is less than 5% of total amount in the prepared vaccine.。
6, the addition that the preparation method of claim 1 bacterin preparation, its feature also are to prepare antibody in the process of antigen antibody complex can surpass antigenic addition.
7, in claim 5,6 the vaccine production method, the technology such as aluminum absorption, precipitation or ultrafiltration of using have been removed irrelevant antibody.
8, the bacterin preparation of claim 1, but human body or microprotein and the polysaccharide or the micromolecular compound of other known human body immunity improving also can be contained.
9, the bacterin preparation of claim 1 be used for being grown up in preparation, the application of the immunotherapy medicaments of the medicine of kidney dialysis patient, organ transplantation patient and hepatitis B high-risk group immunity and preparation chronic hepatitis B patients.
10, the chemical synthetic drug use in conjunction of the bacterin preparation of claim 1 and other chronic hepatitis B patients treatment usefulness.
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| CN 02146247 CN1401389A (en) | 2002-10-17 | 2002-10-17 | Hepatitis B vaccine preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02146247 CN1401389A (en) | 2002-10-17 | 2002-10-17 | Hepatitis B vaccine preparation |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010073119A1 (en) * | 2008-12-23 | 2010-07-01 | Adocia | Stable pharmaceutical composition containing at least one monoclonal antibody and at least one amphiphilic polysaccharide comprising hydrophobic substituents |
| US9493583B2 (en) | 2009-12-23 | 2016-11-15 | Adocia | Anionic polysaccharides functionalized by a hydrophobic acid derivative |
-
2002
- 2002-10-17 CN CN 02146247 patent/CN1401389A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010073119A1 (en) * | 2008-12-23 | 2010-07-01 | Adocia | Stable pharmaceutical composition containing at least one monoclonal antibody and at least one amphiphilic polysaccharide comprising hydrophobic substituents |
| FR2944448A1 (en) * | 2008-12-23 | 2010-10-22 | Adocia | STABLE PHARMACEUTICAL COMPOSITION COMPRISING AT LEAST ONE MONODONAL ANTIBODY AND AT LEAST ONE AMPHIPHILIC POLYSACHARIDE COMPRISING SUBSTITUENTS DERIVED FROM HYDROFOB ALCOHOLS OR HYDROPHOBIC AMINES. |
| US9493583B2 (en) | 2009-12-23 | 2016-11-15 | Adocia | Anionic polysaccharides functionalized by a hydrophobic acid derivative |
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