CN100425288C - Nasal cavity spraying inactivated influenza virus vaccine and its prepn process - Google Patents
Nasal cavity spraying inactivated influenza virus vaccine and its prepn process Download PDFInfo
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- CN100425288C CN100425288C CNB2005100049381A CN200510004938A CN100425288C CN 100425288 C CN100425288 C CN 100425288C CN B2005100049381 A CNB2005100049381 A CN B2005100049381A CN 200510004938 A CN200510004938 A CN 200510004938A CN 100425288 C CN100425288 C CN 100425288C
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Abstract
The present invention provides a novel nasal spray type split influenza virus vaccine and a preparation method thereof. The split influenza virus vaccine comprises the components of cell immune factors, natural polyoses and influenza virus antigens. The human interleukin-2 and the natural polyoses have effectively synergistic effects in the medicine prescription, and increase the permeability of the influenza virus antigens in nasal cavities, so that the degradation of enzymes to the influenza virus antigens is avoided, the effectiveness of midicines is obviously increased, and that the vaccines of the present invention can be favorably used for inoculating biomacromolecule in nasal cavities is disclosed. Human bodies are stimulated to generate local (mucosa) immunoreaction and system immunoreaction, and simultaneously favorable protection effects are obtained.
Description
Technical field:
The present invention relates to a kind of nasal cavity spraying inactivated influenza virus vaccine and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology:
Influenza (influenza) has generation suddenly, propagates characteristics rapidly, little then localized epidemics, and greatly then extend over the entire globe easily leads to complications simultaneously, and severe patient can cause death, and hazardness is very big.Immunity inoculation is the effective ways of flu-prevention, and the prevention of influenza is global public health problem always, and the application influenza vaccines carry out immunoprophylaxis and are subjected to increasing attention.
The spanish influenza of 3 flu outbreak: 1918-1919 once took place in the last century whole world; The Asia influenza of nineteen fifty-seven; The Mao flu of nineteen sixty-eight.The spanish influenza of 1918-1919 is popular, only causes about 5,000 ten thousand people's death in 11 months.The World Health Organization (WHO) gives a warning at present: H 5 N 1 avian influenza may be the strain of next flu outbreak.
Inactivated influenza virus vaccine intramuscular inoculation immunity side reaction is heavier, be unfavorable for especially child, old man or weakling's inoculation on a large scale, and intranasal inoculation has good tolerability, lower side reaction, can be used for child, adult and old people, and easy to use, can inoculate voluntarily, can use among the large tracts of land crowd, be the direction of improving the vaccine of influenza at present in the world.
The vaccinum influenzae inactivatum of Chu Shouing all is the vaccines that need injection inoculation in the market.Even if cracking type influenza vaccines during injection inoculation, still have very big inconvenience, and expense are higher, is unfavorable for higher generalization in numerous crowds.Vaccinum influenzae inactivatum if can be made the nasal spray dosage form, then not only can improve the convenience of vaccination, and be beneficial to the medical treatment cost that reduces the inoculator, reach the vaccinated purpose of higher generalization.
The physiology of the nose function is that air air before arriving lower respiratory tract filters, and adds gentle humidification.The granule of any suction or microorganism can be captured by the rete malpighii in nasal vestibule or covering zone, nose breathing road.The cleaning mechanism that mucomembranous cilium is arranged, rete malpighii will be carried these granules gradually to the pharynx back, down to esophagus, or further arrive gastrointestinal tract.In addition, nasal mucosa also has metabolic function, can help inherent material is transformed into the material that is easy to get rid of.
Nasal septum is divided into two parts that are not connected with people's nasal cavity.Every part is made up of following 3 zones: the first, and nasal vestibule is made up of the inner face zone in nostril, is about 0.6cm
2The second, olfactory region is positioned at the top of nasal cavity the mankind, only is whole nasal region (150
2Cm) about 10%, and, account for 77% dog; The 3rd, the respiratory region is other zone of nasal cavity. and the respiratory region is made up of 3 concha nasalis, superior nasal concha, middle nasal concha and concha nasalis inferior, they become the outer wall of per half nasal cavity.This spiral concha nasalis can make the air-flow of suction contact with the nasal mucosa surface better.
Equally, on all animal membranous types, the nose organ all has similar vestibule structure.Nasal vestibule is coated with stratified squamous cell, and is transformed into pseudo-stratified columnar epithelial cell gradually, and the latter is coated with airway epithelial cell.There is microcilium on the airway epithelial cell surface, and the major part of these cells is coated with cilium equally.These ciliums are that length is the thin thin projection of 4-6mm, can move, and the frequency of per minute vibration is 1000 times.The vibration of every cilium causes very fast travelling forward.The top of cilium can arrive rete malpighii, and the direction of motion of rete malpighii is preceding to the nasal cavity rear portion from nasal cavity.The mobile speed of mucus is the 5mm/ branch, therefore, upgrades 1 time in the every 15-20 of rete malpighii minute.Nasopharynx part also has abundant lymphoid tissue.
Peptide or protein are degraded by enzyme at nasal cavity or by mucosal barrier the time.All contain exopeptidase (exopeptidases) herein, as single and two aminopeptidases, it can be at the N and the disconnected molecule of C end-grain cutting of peptide, and endopeptidase (endopeptidases), and as serine and cysteine, it can destroy interior peptide combination.The degradation half life of peptide is 30 minutes.
Influenza virus is the good object of nasal cavity vaccination by the respiratory mucosa invasion.Nasal meatus is rich in lymphoid tissue, is the target site of intranasal inoculation vaccine, i.e. the relevant lymphoid tissue (NALT) of nose, and it mainly is positioned at pharyngeal lymphoid tissue ring, is called the WaldeyerShi ring.So the advantage of nasal cavity immunity is:
1. nasal mucosa is the antigenic at first position of contact
2. nasal cavity is rich in lymphoid tissue (nose associated lymphoid tissue NALT): promptly Waldeyer encircles
The gland sample or the nasopharynx tonsil
4. bilateral lymph band
5. bilateral pipe dough-making powder or jaw tonsil
6. bilateral tongue tonsil
7 can produce local mucous membrane immunity (sIgA) and systemic immunity (IgG) reaction
8. price is low, patient aspect, non-injection, safety
In our prescription of inactivated influenza virus vaccine nasal mist, added certain density bioadhesion polysaccharide-chitosan.Chitosan is a kind of positively charged linear polysaccharide, and it is a kind of bioadhesion material, can play strong effect with nasal epithelial cells and rete malpighii thereof, to guarantee making medicine carrying passing through nasal mucosa before by mucociliary clearance.In addition, chitosan also can increase the ability of polar medicine cell bypass carrying by the temporary transient opening of tight junction between the epithelial cell.
Also added certain density recombinant human interleukin--2 in our prescription of inactivated influenza virus vaccine nasal mist, the latter's effect has two: one, as the local immunity adjuvant of safety; The 2nd, blood vessel dilating has increased immunogenicity of antigens.
Therefore; influenza antigen among the present invention and Human Inter Leukin-2 and natural polysaccharide exist highly effective synergism in the prescription of medicine; both increased the time of staying of virus antigen in nasal cavity; increased immunogenicity of antigens again; thereby increased the effectiveness of vaccine significantly; disclose vaccine composition proposal of the present invention and can be good at being applied to the intranasal inoculation biomacromolecule; when stimulating body to produce respiratory tract part (mucosa) immunoreation and systemic immunity reaction, has the protection effect of excellent prevention influenza infection.
The prescription of this inactivated influenza virus vaccine spray does not appear in the newspapers on document.
Summary of the invention:
The object of the present invention is to provide a kind of nasal cavity spraying inactivated influenza virus vaccine.
Another object of the present invention is to provide the preparation method of above-mentioned nasal cavity spraying inactivated influenza virus vaccine.
Nasal cavity spraying inactivated influenza virus vaccine of the present invention contains following component: the cellular immunization factor, natural polysaccharide, influenza antigen.
The above-mentioned cellular immunization factor can be human interleukin, recombinant human interleukin, human interferon, recombinant human interferon alpha 2.Preferred Human Inter Leukin-2 or recombinant human interleukin--2.
Natural polysaccharide can be cellulose, starch, chitin, chitosan and derivant thereof, perhaps can select the combination in any of aforementioned natural polysaccharide, and these are combined in varying degrees all can reach the effect that product of the present invention has.Preferred chitin, the chitosan of using.
The influenza antigen that nasal cavity spraying inactivated influenza virus vaccine of the present invention contains comprises: totivirus antigen, lytic virus antigen or viral sub-units antigen.Preferred lytic virus antigen.Influenza antigen is to form according to the Strain that WHO recommends, and both can prepare voluntarily, also can directly buy to obtain.
The preparation method of lytic virus has been sophisticated technology, and all commercializations both at home and abroad comprise unit price lytic virus and trivalent lytic virus.The objective of the invention is to use that existing lytic virus and natural polysaccharide and other adjuvant are mixed in the prior art, preparation is suitable for the spraying medicament of nasal absorption.
The weight content of above component in final preparation is:
The cellular immunization factor 10
4-10
6Unit/L
Natural polysaccharide 0.1-10%
Influenza antigen 30-70%
Remainder is a buffer solution.
Preferred content is:
The cellular immunization factor 10
4-10
6Unit/L
Natural polysaccharide 0.5-5%
Influenza antigen 40-60%
Remainder is a buffer solution.
Most preferred content is:
The cellular immunization factor 10
5Unit/L
Natural polysaccharide 1%
Influenza antigen 50%
Remainder is a buffer solution.
Described buffer solution is that pH is 7 phosphate buffer solution;
Described phosphate buffer solution can further contain the human serum albumin of 0.05-0.10% weight ratio, as the protective agent of vaccine antigen composition.
Described phosphate buffer solution can further contain acceptable adjuvant on the pharmaceutics, and for example, benzyl alcohol, mannitol or the like, adjuvant total content are the 0.1-5% weight ratio.
Buffer solution of the present invention does not contain any to nasal mucosa antiseptic excitatory.
The preparation method of nasal cavity spraying inactivated influenza virus vaccine of the present invention is with said components: the cellular immunization factor, natural polysaccharide, influenza antigen are operated according to the nasal mist preparation method of describing in the pharmaceutics.
The cellular immunization factor in the said method can be human interleukin, recombinant human interleukin, human interferon, recombinant human interferon alpha 2.Preferred Human Inter Leukin-2 or recombinant human interleukin--2.
Natural polysaccharide in the said method can be cellulose, starch, chitin, chitosan and derivant thereof, perhaps can select the combination in any of aforementioned natural polysaccharide, and these are combined in varying degrees all can reach the effect that product of the present invention has.Preferred chitin, the chitosan of using.
Influenza antigen in the said method comprises: totivirus antigen, lytic virus antigen or viral sub-units antigen.Preferred lytic virus antigen.Influenza antigen is to form according to the Strain that WHO recommends, and both can prepare voluntarily, also can directly buy to obtain.
The preparation method of lytic virus has been sophisticated technology, and all commercializations both at home and abroad comprise unit price lytic virus and trivalent lytic virus.The objective of the invention is to use that existing lytic virus and natural polysaccharide and other adjuvant are mixed in the prior art, preparation is suitable for the spraying medicament of nasal absorption.
The weight content of above component in final preparation is:
The cellular immunization factor 10
4-10
6Unit/L
Natural polysaccharide 0.1-10%
Influenza antigen 30-70%
Remainder is a buffer solution.
Preferred content is:
The cellular immunization factor 10
4-10
6Unit/L
Natural polysaccharide 0.5-5%
Influenza antigen 40-60%
Remainder is a buffer solution.
Most preferred content is:
The cellular immunization factor 10
5Unit/L
Natural polysaccharide 1%
Remainder is a buffer solution.
Described buffer solution is that pH is 7 phosphate buffer solution;
Described phosphate buffer solution can advance-go on foot to contain the human serum albumin of 0.05-0.10% weight ratio, as the protective agent of vaccine antigen composition.
Described phosphate buffer solution can further contain acceptable adjuvant on the pharmaceutics, and for example, benzyl alcohol, mannitol or the like, adjuvant total content are the 0.1-5% weight ratio.
Buffer solution of the present invention does not contain any to nasal mucosa antiseptic excitatory.
The influenza virus culture method has two kinds, i.e. cell culture method and cultivation in the chick embryo; Cell culture method has the big advantage of cultivation amount, and results liquid viral hemoagglutination is tired and can be reached 1: 256; The culture efficiency of cultivation in the chick embryo is higher relatively, and results liquid hemagglutinative titer can reach 1: 640 even above 1: 1000.
The preparation of influenza antigen of the present invention is carried out according to following process: seed bank foundation, Virus culture and results, inactivation of virus, viral purification, virolysis, the alcoholization of viromembrane antigen, decomposition agent are removed (univalent vaccine stock solution), mixed preparing.
Influenza antigen of the present invention also can directly be commercially available.
Joining of each component variable concentrations is the best of breed of studying through repeatedly mutually in the preparation method of product of the present invention.Can produce best immune effect.
Nasal cavity spraying inactivated influenza virus vaccine component of the present invention be have synergistic mutually: the cellular immunization factor is as immunological adjuvant and vasodilation; Natural polysaccharide is as the expander in bioadhesion material and epithelial cell gap, unite use with influenza antigen, both increased the time of staying of virus antigen in nasal cavity, increased immunogenicity of antigens again, thereby increased the effectiveness of vaccine significantly, also reduced the zest of vaccine spray nasal membrane.
Description of drawings:
Fig. 1 is the postvaccinal average IgA titre of mice collunarium of each group
Fig. 2 is the postvaccinal average IgA titre of mice collunarium of each group
Fig. 3 is that the postvaccinal blood clotting of the mice collunarium of each group suppresses titre (HI)
The specific embodiment:
Embodiment 1
Get 10000 people from unit recombinant interleukin 2s, this people's recombinant interleukin 2 is so kind as to give by Beijing plan far away pharmaceutcal corporation, Ltd; 1% chitosan is available from U.S. Sigma company, and molecular weight is 150kD, and is deacetylated more than 85%, and buffer is the phosphoric acid solution that contains weight ratio 1% benzyl alcohol, 1% mannitol, 0.05% human serum albumin, and its pH value is 7.0;
Above-mentioned three mixes according to 1: 1 volume ratio with trivalent cracking influenza virus hemagglutinin antigen (available from Bath moral institute) after mixing, preparation trivalent cracking inactivated influenza virus vaccine nasal mist, and every volume is 100 microlitres, is used for nasal cavity immunity.
Embodiment 2
Use the popular strains of influenza viruses that WHO recommends: H3N2 influenza A virus, H1N1 influenza A virus and Influenza B virus, three kinds of viruses are inoculated 9-11 age in days chick embryo allantois respectively, after 37C cultivates 48 hours, collect allantoic fluid respectively, use the formalin inactivation of viruses, adopt SDS influenza virus cracking agent lytic virus granule, separate respectively again and purification, obtain lytic virus;
With 5*10
5The pH of the human interferon-alpha-2 b of unit, 5g starch adding 500mL is 7.0 phosphate buffer solution, and phosphate buffer solution contains benzyl alcohol, the 5g mannitol of 1g human serum albumin, 1g;
Get the 500g lytic virus, add above-mentioned buffer, make trivalent cracking inactivated influenza virus vaccine nasal spray, agent is used for nasal cavity immunity.
Embodiment 3
Use the popular then strains of influenza viruses that WHO recommends: H3N2 influenza A virus, H1N1 influenza A virus and Influenza B virus, three kinds of viruses are inoculated 9-11 age in days chick embryo allantois respectively, after 37C cultivates 48 hours, collect allantoic fluid respectively, extract the viral hemagglutinin (HA) of three strain virus respectively;
Get 10
4The pH of people from unit recombinant interleukin 2 (plan far away pharmaceutcal corporation, Ltd in Beijing is so kind as to give), 10g chitin adding 500mL is 7.0 phosphate buffer solution, and phosphate buffer solution contains benzyl alcohol, the 0.5g mannitol of 0.6g human serum albumin, 5g;
Get the 500g lytic virus, add above-mentioned buffer, make trivalent cracking inactivated influenza virus vaccine nasal spray, agent is used for nasal cavity immunity.
Embodiment 4
Use the popular then strains of influenza viruses that WHO recommends: H3N2 influenza A virus, H1N1 influenza A virus and Influenza B virus, adopt that gene recombination technology is cloned respectively, recombinated, the HA of expression, purification three influenzae strain viruses;
Get 10
6The pH of unit human interferon alpha 1 b, 3g chitosan (U.S. Sigma company, molecular weight are 150kD, deacetylated 85%) adding 500mL is 7.0 phosphate buffer solution;
Get the 500g lytic virus, add above-mentioned buffer, make trivalent cracking inactivated influenza virus vaccine nasal spray, agent is used for nasal cavity immunity.
Comparative example 1
According to the method for embodiment 1, preparation matched group 1 nasal mist is used for nasal cavity immunity.This matched group medicament directly uses buffer and influenza virus hemagglutinin antigen mixed, does not contain people's recombinant interleukin 2 and chitosan, and all the other are with embodiment 1.
With 4.5 microgram influenza virus hemagglutinin antigens, cumulative volume is 100 microlitres, is used for the muscle immunity, organizes 2 in contrast simultaneously, is used for the nasal cavity immunity effect according to embodiment 1 product.
The immunization protocol of this comparative example is medicament difference collunarium inoculation 8 female adult BALB/c mouse (6-8 week is available from Beijing animal institute) nostril with embodiment 1 product and matched group 1, every hole 50 microlitres; Matched group 2 is by 8 female adult BALB/c mouse of 100 microlitre intramuscular inoculations (injection) (6-8 week).
Every mice equivalent nasal cavity immunity secondary in 1 group of embodiment and the matched group 1, be 14 days interval.Matched group 2 an intramuscular injection immunity once.
Sampling mode is for gathering mouse orbit serum, the antigenic blood clotting of antihemagglutinin suppresses the IgG titre of titre (HI) and resisiting influenza virus in the mensuration serum, collect mouse lung trachea washing liquid (with 1 milliliter of phosphate buffer pH7.0), measure the IgA titre of resisiting influenza virus.Sampling time be after the immunity for the second time the 15th day.
Mucosal immunoreaction (IgA) and systemic immunity reaction (IgG) result that mice produces have been measured with enzyme linked immunological adsorption method (ELISA).As negative control, after the background of eliminating analytical method, determine the antibody titer of the resisiting influenza virus of serum and trachea washing liquid with the optical density absorption value with the serum of mice and pulmonary's trachea washing liquid before the immunity.
The result of table 1 and Fig. 1 antibody response shows, after the immunity second time, inoculates the average titer of back IgA greater than 200 from the mice collunarium of 1 group of embodiment.Reply (average titer of IgA is less than 4) from no resisiting influenza virus in the mice collunarium inoculation back trachea washing liquid of matched group 2,3.
Table 1:IgA testing result OD value
| Extension rate | Negative | Matched group 2 | Matched group 1 | Embodiment 1 |
| 4 | 0.29 | 0.1895 | 0.246 | 0.7835 |
| 16 | 0.148 | 0.1575 | 0.1435 | 0.559 |
| 64 | 0.166 | 0.1155 | 0.115 | 0.375 |
| 256 | 0.1455 | 0.1355 | 0.121 | 0.2085 |
The result of table 2 and Fig. 2 antibody response shows, after the immunity second time, from the postvaccinal average IgG titre of the mice collunarium of 1 group of embodiment with compare no significance difference from the average IgG titre after the injection of the mouse muscle of matched group 2, and replying by force relatively from mice (not containing people's recombinant interleukin 2 and chitosan) the collunarium inoculation back serum IgG of matched group 1.
Table 2:IgA testing result OD value
| Extension rate | Matched group 2 | Matched group 1 | Embodiment 1 |
| 100 | 0.608 | 0.3465 | 0.6135 |
| 400 | 0.332 | 0.2175 | 0.353 |
| 1600 | 0.1785 | 0.1555 | 0.1795 |
| 6400 | 0.1115 | 0.1 | 0.1215 |
| 25600 | 0.0995 | 0.096 | 0.1 |
| 102400 | 0.135 | 0.091 | 0.0945 |
| Blank | 0.09 |
The antigenic blood clotting inhibition of antihemagglutinin titre (HI) result shows in the serum that Fig. 3 measures, after the immunity second time, the highest from the average HI titre after the mouse muscle injection of matched group 2, it is 1: 320, secondly be from the postvaccinal average HI titre of the mice collunarium of 1 group of embodiment (1: 160), contrast quite (1: 40) from average HI titre after the mice collunarium inoculation (not containing people's recombinant interleukin 2 and chitosan) of matched group 1 and the seronegativity of exempting from preceding mice.It is generally acknowledged that the HI titre has protective effect greater than 1: 80 immune serum.
Comparative example 2
Matched group 1,2 is with comparative example 1.
With 100LD50 (half lethal dose) Mus lung adapted strain A/PR/8/34 (H
1N
1) counteracting toxic substances, the above immune mouse (matched group 1,2,1 group of embodiment) of attacking of blood clotting titre 1: 2048,4 not immune mouse as negative control.
The counteracting toxic substances time is immunity for the second time after 57 days, the counteracting toxic substances method be with ether with mouse anesthesia, the Mus lung adapted strain 100ul after will diluting with syringe splashes into the mice nostril, the 50ul/ nostril is observed day by day.Behind the counteracting toxic substances 10 days, 4 mices are all dead in the matched group 1,2,2 death among 1 group of the embodiment, and 2 survivals, concrete outcome sees the following form 3.
Table 3: immune mouse challenge test result
Though 1 group of embodiment and matched group 2 do not have 100% protection efficient, the result shows that still the nasal cavity immunity protection effect of 1 group of embodiment is than matched group 2 height.
Claims (13)
1, a kind of nasal cavity spraying inactivated influenza virus vaccine is characterized in that, described vaccine contains following component:
The cellular immunization factor 10
4-10
6Unit/L
Natural polysaccharide 0.1-10% weight ratio
Influenza antigen 30-70% weight ratio
Remainder is a buffer solution;
The described cellular immunization factor is Human Inter Leukin-2 or recombinant human interleukin--2.
2, vaccine according to claim 1 is characterized in that, described natural polysaccharide is cellulose, starch, chitin or chitosan, perhaps selects the combination in any of aforementioned natural polysaccharide.
3, vaccine according to claim 2 is characterized in that, described natural polysaccharide is chitin or chitosan.
4, vaccine according to claim 1 is characterized in that, described influenza antigen is totivirus antigen, lytic virus antigen or viral sub-units antigen.
5, vaccine according to claim 4 is characterized in that, described influenza antigen is a lytic virus antigen.
6, vaccine according to claim 1 is characterized in that, described vaccine contains following component:
The cellular immunization factor 10
4-10
6Unit/L
Natural polysaccharide 0.5-5% weight ratio
Influenza antigen 40-60% weight ratio
Remainder is a buffer solution;
The described cellular immunization factor is Human Inter Leukin-2 or recombinant human interleukin--2.
7, vaccine according to claim 6 is characterized in that, described vaccine contains following component:
The cellular immunization factor 10
5Unit/L
Natural polysaccharide 1% weight ratio
Influenza antigen 50% weight ratio
Remainder is a buffer solution;
The described cellular immunization factor is that the people is from cytokine-2 or recombinant human interleukin--2.
According to claim 1,6 or 7 any described vaccines, it is characterized in that 8, described buffer solution is that pH is 7 phosphate buffer solution.
9, vaccine according to claim 8 is characterized in that, described phosphate buffer solution also further contains the human serum albumin of 0.05-0.10% weight ratio.
10, according to Claim 8 or 9 described vaccines, it is characterized in that described buffer solution contains acceptable adjuvant on the pharmaceutics, the adjuvant total content is the 0.1-5% weight ratio.
11, vaccine according to claim 10 is characterized in that, described adjuvant is benzyl alcohol or mannitol, and the adjuvant total content is the 0.1-5% weight ratio.
12, the preparation method of any described vaccine of claim 1-11 is characterized in that, comprises the cellular immunization factor and natural polysaccharide are joined in the buffer solution, adds influenza antigen then, promptly makes nasal cavity spraying inactivated influenza virus vaccine.
13, the purposes of any described vaccine of claim 1-11 aspect preparation treatment or prevention influenza medicine.
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| CN101274097B (en) * | 2008-05-23 | 2011-02-09 | 崔栋 | Atomizing grippe vaccine composition and preparation thereof |
| CN101391103B (en) * | 2008-07-31 | 2013-07-24 | 张可 | Medicine composition for preventing and treating AIDS viral infection |
| CN113117093B (en) * | 2019-12-31 | 2024-02-09 | 辽宁成大生物股份有限公司 | Promoter suitable for nasal mucosa delivery of influenza vaccine |
| CN115725660B (en) * | 2022-10-09 | 2023-07-07 | 天津中逸安健生物科技有限公司 | Preparation method of recombinant influenza subunit vaccine |
| CN116966287B (en) * | 2022-11-10 | 2024-07-26 | 江苏华诺泰生物医药科技有限公司 | Cracking method for influenza virus cracked vaccine |
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| CN1344155A (en) * | 1999-01-27 | 2002-04-10 | 概念股份公司 | Transnasal transport/immunisation with highly adaptable carriers |
| WO2004103271A2 (en) * | 2003-04-18 | 2004-12-02 | Norwood Immunology, Ltd. | Disease prevention and vaccination prior to thymic reactivations |
| CN1555271A (en) * | 2001-09-17 | 2004-12-15 | Interleukin-12 as a veterinary vaccine adjuvant |
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2005
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1159761A (en) * | 1994-10-04 | 1997-09-17 | 麦迪瓦赫丁公司 | Vaccine compositions |
| CN1201396A (en) * | 1995-11-01 | 1998-12-09 | 麦迪瓦赫丁公司 | Influenza vaccine compositions |
| CN1298307A (en) * | 1998-03-05 | 2001-06-06 | 俄亥俄医学院 | Enhancement of immunity by intranasal inoculation of IL-12 |
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| WO2004103271A2 (en) * | 2003-04-18 | 2004-12-02 | Norwood Immunology, Ltd. | Disease prevention and vaccination prior to thymic reactivations |
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