CN101095950A - Hydrophobia vaccine freezing drying preparations for stable human beings and the preparations thereof - Google Patents
Hydrophobia vaccine freezing drying preparations for stable human beings and the preparations thereof Download PDFInfo
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- CN101095950A CN101095950A CNA2006100470873A CN200610047087A CN101095950A CN 101095950 A CN101095950 A CN 101095950A CN A2006100470873 A CNA2006100470873 A CN A2006100470873A CN 200610047087 A CN200610047087 A CN 200610047087A CN 101095950 A CN101095950 A CN 101095950A
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Abstract
The invention relates to a kind of hydrophobia vaccine for human, which in detail relates to a freeze-drying hydrophobia vaccine for human and its preparation method. It is contained in physiological soluble buffer solution with pH being 7-8, the sodium chloride weight proportion is 0.4-1.0%, one or several from mycose, sucrose, gelatin, maltose and dextran is used as stabilizing agent, the concentration is 0.5-5%; the weight proportion of shaping agent for freeze-drying agent is 1-5%, and the purified hydrophobia viral antigen concentration is 4-20 IU per ml.
Description
Technical field
The present invention relates to Antirabic Vaccine's preparation, on specifically a kind of do not contain human albumin, Antirabic Vaccine's lyophilized formulations that can mix, stable storage and preparation thereof.
Background technology
Rabies vaccine is the application cell culturing engineering, carry out the cultivation and the results of rabies virus, behind special purification and deactivation, add certain density human albumin and make various liquid and lyophilized formulations, be a kind ofly to be used to prevent and to treat the immune vaccine that is exposed to behind the rabies virus, but the effective stimulus body produces anti-rabies virus antibody clinically, the prevention rabies.
The existing at home and abroad corresponding launch of stable rabies vaccine preparation; wherein all contain the human serum albumin as stabilizing agent; end user's serum albumin makes complex manufacturingization as stabilizing agent; as a kind of blood products; the human albumin can bring the blood disease pollution problems; have and pollute and pathophorous potential danger, the particularity of vaccine medicine makes it propose requirements at the higher level to stabilizing agent or protective agent.At present except that end user's serum albumin, sucrose, glucosan, manna are pure, sorbitol etc. often is applied in the protide biological product, as interferon, EPO, IL-2 etc., documents and materials such as Chinese patent CN1160355A, CN85101930 all have report in various degree.But replacing conventional human serum albumin's stabilizing agent of using in the rabies vaccine preparation does not still have relevant report.
Summary of the invention
The object of the present invention is to provide a kind of production not contain method human albumin, Antirabic Vaccine's novel formulation that can mix, stable storage; do protectant rabies vaccine stability with the employing human serum albumin by experiment and compare, proved its advantage.
For achieving the above object, stable Antirabic Vaccine of the present invention is specifically composed as follows:
Comprise in the buffer of the pH7.0-8.0 that can mix on physiology, weight sodium chloride concentration is 0.4-1.0%, and one or more in trehalose, sucrose, gelatin, maltose, the glucosan are made stabilizing agent, and consumption concentration is 0.5%-5%; Lyophilized formulations excipient, consumption concentration are 1%-5%; The inactivated rabies virus antigen of purification, every milliliter of content is 4-20 IU.
Wherein to come from PV2061 be strain to the inactivated rabies virus antigen of purification, and aG strain and CTN strain; Buffer system selects pH7.0-8.0 scope buffering right, can be material and combinations such as phosphoric acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, glycine.Buffer is best phosphate buffer, and sodium chloride concentration is preferably 0.4-0.8%, and stabilizing agent is preferably weight concentration 1-5% trehalose and/or weight concentration 1-5% sucrose; Excipient can be weight concentration 1-5% dextran, mannitol and/or glucosan usually.
The preparation of described Antirabic Vaccine's lyophilized formulations, prepare the buffer of pH7.0-8.0 earlier, sodium chloride concentration is 0.4-1.0%, add stabilizing agent, add freeze-dried excipient again, use the degerming of 0.1-0.2um membrane filtration then, the inactivated rabies virus antigen that adds purification at last, every milliliter of antigenic content is 4-20 IU, and mixing is abundant and be distributed into bottle, adopts the freeze dryer vacuum freeze-drying to make a kind of stable Antirabic Vaccine's lyophilized formulations that does not contain the human serum albumin at last.
Bottled preparation specification can be every bottle of 0.5ml or 1.0ml.
The present invention has following advantage:
1. the stabilizing agent of the present invention's employing is that non-blood extracts composition, and rabies virus antigen is had good stablizing effect, and the application concentration of stabilizing agent is more than 1%, and optimum is 2-4%.Use the contrast experiment by different stabilizing agent, as can be seen to the stablizing effect of rabies virus antigen near or slightly be better than and adopt the human albumin to make stabilizing agent, and do not have the pathogenic problem of blood contamination and transmitted virus.
2. the Antirabic Vaccine's preparation among the present invention can also further add isotonic agent, micromolecule saccharide and salt etc.Buffer system selects pH7.0-8.0 scope buffering right, can be material and combinations such as phosphoric acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, glycine; Be preferably sodium dihydrogen phosphate and sodium hydrogen phosphate buffer system, pH scope after two kinds of combinations is consistent with human internal environment's pH value, can reduce zest, can not cause uncomfortable reaction after the injection human body, but this system complexation of metal ions and prevent autooxidation simultaneously.
By study on the stability, can find out that this buffer system has the effect of stablizing whole preparation system, can not cause antigenic gathering of high concentration virus and precipitation, add corresponding excipient and can be made into freeze-dried formulation.
3. rabies vaccine preparation stabilization of the present invention, low toxicity, the low side reaction incidence rate of clinical preceding experiment, through the long-time stability laboratory observation, it is stable to show brilliance, can equally use to existing similar vaccine.
4. bacterin preparation of the present invention makes the inoculator produce antibody in advance than the vaccine that contains adjuvant in clinical practice, is beneficial to the prevention rabies; Applying biological micromolecule in finished product preparation; replace the human albumin as monosaccharide, polysaccharide, alcohols and cook protective agent; both the good tissue intermiscibility was arranged with human body; reduced the cost of finished product; simultaneously can avoid using the human albumin and bring potential haematogenous secondary infection case, clinical practice is more safe and reliable in epidemic prevention.
The specific embodiment
Describe content of the present invention by the following examples in detail, but these embodiment are not to be limitation of the present invention.
Embodiment 1:
Adopt the phosphate-buffered liquid systems of pH7.2 scope, sodium chloride concentration is 0.8%, add 2% trehalose again, 2% sucrose adds 3% dextran again and does freeze-dried excipient, use the degerming of 0.1-0.2um membrane filtration then, add inactivated rabies virus antigen (deriving from the pv2061 strain) again to 12IU/ml, mixing is abundant and be distributed into every bottle of 0.5 milliliter of specification preparation, through lyophilization, make the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measure its immunizing potency of preparation.
Embodiment 2:
According to embodiment 1, replace trehalose with 1% maltose, replace dextran to do excipient with 3% glucosan, make the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measure its immunizing potency.
Embodiment 3:
According to embodiment 1, replace trehalose with 3% gelatin, make the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measure its immunizing potency.
Embodiment 4:
According to embodiment 1, replace dextran to do excipient with 3% mannitol, 1% glucosan replaces trehalose, and the packing specification replaces 0.5ml with 1ml, makes the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measures its immunizing potency.
Embodiment 5:
According to embodiment 1, with the rabies virus antigen of the rabies virus antigen replacement PV2061 strain that derives from the CTN strain, make the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measure its immunizing potency.
Embodiment 6:
According to embodiment 1, with the rabies virus antigen of the rabies virus antigen replacement PV2061 strain that derives from the aG strain, make the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measure its immunizing potency.
Embodiment 7:
According to embodiment 1, increase by 1% maltose composition, make the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measure its immunizing potency.
Embodiment 8:
According to embodiment 1, replace dextran to do excipient with 3% glucosan, make the rabies vaccine lyophilized formulations that does not contain the human serum albumin, measure its immunizing potency.
Embodiment 9:
According to embodiment 1, adopt 3% human serum albumin to replace trehalose, other is constant, makes the rabies vaccine lyophilized formulations that contains the human serum albumin, measures its immunizing potency, in contrast benchmark.
Rabies vaccine lyophilized formulations part according to above embodiment preparation was stored 0 month, 6 months, 12 months, 18 months, 24 months for 4 ℃, a part is placed on stored for 2 weeks with all around in 37 ℃ of incubators, adopt the interior immunization of NIH mice body to carry out stable efficacy determinations to after date.
Data by stability experiment are investigated, and adopt the stability of the rabies vaccine of one or more non-haematogenous stabilizing agents preparations, near or do protectant lyophilized formulations a little more than using the human serum albumin.
The stability experiment tables of data:
1. the stability result of rabies vaccine (embodiment 1-9)
(the investigation condition is 4 ℃, 0-24 month; Render a service initial standard 6IU/0.5ml.)
| Investigate the date | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | Example 8 | Example 9 |
| 0 month | 6.4 | ?6.1 | ?5.8 | ?6.2 | ?6.3 | ?5.8 | ?5.8 | ?6.2 | ?6.2 |
| 6 months | 6.1 | ?5.7 | ?5.7 | ?5.5 | ?5.3 | ?5.2 | ?5.4 | ?5.5 | ?5.8 |
| 12 months | 5.4 | ?5.0 | ?5.3 | ?4.9 | ?4.6 | ?5.0 | ?4.8 | ?4.8 | ?5.2 |
| 18 months | 4.5 | ?4.2 | ?4.5 | ?3.7 | ?4.0 | ?4.1 | ?3.8 | ?3.8 | ?4.5 |
| 24 months | 3.1 | ?2.7 | ?3.0 | ?2.6 | ?2.6 | ?2.8 | ?2.5 | ?2.7 | ?2.9 |
2. the stability result of rabies vaccine (embodiment 1-9)
(the investigation condition is 37 ℃, 0,2,4 weeks; Render a service initial standard 6IU/0.5ml.)
| Investigate the date | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | Example 8 | Example 9 |
| 0 week | 6.4 | ?6.1 | ?5.8 | ?6.2 | ?6.3 | ?5.8 | ?5.8 | ?6.2 | ?6.2 |
| 2 weeks | 5.2 | ?5.0 | ?4.9 | ?4.5 | ?4.7 | ?4.6 | ?4.3 | ?4.6 | ?5.1 |
| 4 weeks | 3.0 | ?2.6 | ?2.8 | ?2.5 | ?2.5 | ?2.6 | ?2.5 | ?2.6 | ?2.9 |
| 6 weeks | 2.5 | ?2.2 | ?2.4 | ?2.2 | ?2.0 | ?2.3 | ?2.0 | ?2.1 | ?2.6 |
Claims (7)
1. stable Antirabic Vaccine's lyophilized formulations, it is characterized in that: comprise in the buffer of the pH7.0-8.0 that can mix on the physiology, weight sodium chloride concentration is 0.4-1.0%, in trehalose, sucrose, gelatin, maltose, the glucosan one or more are made stabilizing agent, and consumption concentration is 0.5%-5%; Lyophilized formulations excipient, consumption concentration are 1%-5%; The inactivated rabies virus antigen of purification, every milliliter of content is 4-20 IU.
2. according to the described Antirabic Vaccine's lyophilized formulations of claim 1, it is characterized in that: wherein to come from PV2061 be strain to the inactivated rabies virus antigen of purification, and aG strain and CTN strain.
3. according to the described Antirabic Vaccine's lyophilized formulations of claim 1, it is characterized in that: wherein buffer is a phosphate buffer, sodium chloride concentration 0.4-0.8%.
4. according to the described Antirabic Vaccine's lyophilized formulations of claim 1, it is characterized in that: wherein stabilizing agent is weight concentration 1-5% trehalose and/or weight concentration 1-5% sucrose.
5. according to the described Antirabic Vaccine's lyophilized formulations of claim 1, it is characterized in that: wherein excipient is weight concentration 1-5% dextran, mannitol and/or glucosan.
6. the preparation of the described Antirabic Vaccine's lyophilized formulations of claim 1, it is characterized in that: the buffer of preparing pH7.0-8.0 earlier, sodium chloride concentration is 0.4-1.0%, add stabilizing agent, add freeze-dried excipient again, use the degerming of 0.1-0.2um membrane filtration then, the inactivated rabies virus antigen that adds purification at last, every milliliter of antigenic content is 4-20 IU, mixing is abundant and be distributed into bottle, adopts the freeze dryer vacuum freeze-drying to make a kind of stable Antirabic Vaccine's lyophilized formulations that does not contain the human serum albumin at last.
7. according to the preparation of the described Antirabic Vaccine's lyophilized formulations of claim 6, it is characterized in that: described bottled preparation specification is every bottle of 0.5ml or 1.0ml.
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