CN109498804B - Temperature response type rabies vaccine delivery system - Google Patents
Temperature response type rabies vaccine delivery system Download PDFInfo
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- CN109498804B CN109498804B CN201811472126.3A CN201811472126A CN109498804B CN 109498804 B CN109498804 B CN 109498804B CN 201811472126 A CN201811472126 A CN 201811472126A CN 109498804 B CN109498804 B CN 109498804B
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- 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
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- 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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
- A61P31/14—Antivirals for RNA viruses
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- 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
- A61K2039/55505—Inorganic adjuvants
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- 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
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/20011—Rhabdoviridae
- C12N2760/20111—Lyssavirus, e.g. rabies virus
- C12N2760/20134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
The invention discloses a temperature response type rabies vaccine delivery system. The invention provides a rabies vaccine temperature-sensitive delivery system, which comprises the following solutes: PLGA-PEG-PLGA, manganese ions and rabies vaccine antigen; the proportion of the PLGA-PEG-PLGA, the manganese ions and the rabies vaccine antigen is 50-200 mg: 20-100. mu.g: 0.3-5 IU. According to the delivery system prepared by the invention, the antibody production amount after the second injection can achieve the effect of the rabies vaccine sold in the market after the fourth injection; when the antigen contained in the vaccine is injected when the dosage is reduced to one tenth of that of the commercial rabies vaccine, the antibody titer is equivalent to that of the commercial vaccine product. The rabies vaccine delivery system can reduce the times of immunity and keep the original immune response intensity on the basis of keeping the same single dose of commercially available rabies vaccine.
Description
Technical Field
The invention belongs to the crossing field of biological agents and biomedicine, and particularly relates to a temperature response type rabies vaccine delivery system.
Background
Rabies is a fatal disease caused by rabies virus infection, the death rate after the disease is almost 100 percent, and an effective treatment method is not available in the world until now. Therefore, rabies vaccine is required to be injected immediately after being bitten by a rabies or an animal with unknown toxicity. Rabies vaccines are mostly used for post-exposure immunization, so the faster the speed of an immune response in a human body, the higher the antibody titer, the better the prophylactic effect.
At present, the research of vaccine adjuvants is also one of hot spots, and the research comprises the traditional aluminum adjuvants, novel microsphere adsorption adjuvants, gel adjuvants such as chitosan and the like, and various adjuvants have the characteristics and the defects: for example, the traditional adjuvant has poor immune effect, the microsphere adjuvant has complex manufacturing process, and the gel adjuvant has the characteristics of long retention time, controllable release and the like.
The immunization mode of the rabies vaccine clinically applied is 0 th, 3 th, 7 th, 14 th and 28 th days for immunization injection, the defects of more injection times, low immunization effect and the like exist, with the progress of people-oriented social concept, the pain of patients is reduced, and the improvement of compliance is one of the directions of medical progress.
Disclosure of Invention
An object of the invention is to provide a temperature-sensitive delivery system for rabies vaccine.
The rabies vaccine temperature-sensitive delivery system provided by the invention comprises the following solutes: PLGA-PEG-PLGA, manganese ions and rabies vaccine antigen;
the proportion of the PLGA-PEG-PLGA, the manganese ions and the rabies vaccine antigen is 50-200 mg: 20-100. mu.g: 0.3-5 IU.
In the rabies vaccine temperature-sensitive delivery system, the manganese ions are Mn 2+ Exist in the form of (1).
In the rabies vaccine temperature-sensitive delivery system, the molecular weight of PLGA in the PLGA-PEG-PLGA is about 2000, and the molecular weight of PEG is about 1500.
In the rabies vaccine temperature-sensitive delivery system, the solute further comprises an adjuvant;
the adjuvant is Al (OH) 3 An adjuvant;
the Al (OH) 3 The proportion of the adjuvant to the rabies vaccine antigen is 5-30 mg: 0.3-5 IU.
The rabies vaccine temperature-sensitive delivery system also comprises a solvent;
the rabies vaccine temperature-sensitive delivery system consists of a solute and a solvent;
the solvent is physiological saline.
The response temperature of the rabies vaccine temperature-sensitive delivery system is 25-40 ℃.
Another object of the invention is to provide a method for preparing the rabies vaccine temperature-sensitive delivery system.
The method provided by the invention comprises the following steps:
1) preparing a vaccine delivery system of a composite aluminum adjuvant and a rabies vaccine antigen solution containing manganese ions;
the vaccine delivery system of the composite aluminum adjuvant is prepared by mixing PLGA-PEG-PLGA hydrosol and Al (OH) 3 Uniformly mixing the adjuvants to obtain a vaccine delivery system of the composite aluminum adjuvant;
the PLGA-PEG-PLGA hydrosol is obtained by dissolving PLGA-PEG-PLGA in physiological saline, wherein the PLGA-PEG-PLGA has a mass volume percentage of 10-30% (or a concentration of 100-300 mg/ml);
the manganese ion-containing rabies vaccine antigen solution is prepared by uniformly mixing a rabies vaccine antigen, manganese chloride and physiological saline to obtain a manganese ion-containing rabies vaccine antigen solution, wherein the concentration of the rabies vaccine antigen is 0.3-5IU/ml, and the concentration of the manganese chloride is 20-100 mu g/ml;
2) and mixing the vaccine delivery system of the composite aluminum adjuvant with the rabies vaccine antigen solution containing the manganese ions to obtain the rabies vaccine temperature-sensitive delivery system.
In the method, in the rabies vaccine temperature-sensitive delivery system, the ratio of PLGA-PEG-PLGA: the Al (OH) 3 : the rabies vaccine antigen: the proportion of the manganese chloride is 50-200 mg: 5-30 mg: 0.3-5 IU: 20-100 mug.
In the above method, in the step 2), the PLGA-PEG-PLGA hydrosol and Al (OH) 3 The proportion of the adjuvant is 50-200 mg: 5-30 mg;
in the step 3), the volume ratio of the vaccine delivery system of the composite aluminum adjuvant to the rabies vaccine antigen solution containing the manganese ions is 1: 3-1: 4.
the application of the rabies vaccine temperature-sensitive delivery system in preparing immune human or animal products is also within the protection scope of the invention;
or, the application of the rabies vaccine temperature-sensitive delivery system in preparing products for preventing and treating rabies is also the protection scope of the invention;
or, the application of the rabies vaccine temperature-sensitive delivery system in preparing products for improving the titer or content of the antibody generated after the immunization of human or animals is also within the protection range of the invention;
or, the invention also provides a method for delivering the rabies vaccine temperature-sensitive delivery system, which is to deliver the rabies vaccine temperature-sensitive delivery system into an animal body.
The delivery mode is subcutaneous immunization.
The technical principle of the invention is as follows:
firstly, a material with a certain temperature change characteristic is dissolved in physiological saline for injection according to 20 percent at room temperature, the material is fully swelled at 4 ℃, and MnCl is compounded after a colorless transparent solution is formed by utilizing the phase change characteristic to the temperature change generated by the solubility difference between poly (lactic-co-glycolic acid) and PEG in PLGA-PEG-PLGA block copolymer in water 2 And rabies vaccine antigen, namely the temperature response type rabies vaccine can be formed.
According to the delivery system prepared by the invention, the antibody production amount after the second injection can achieve the effect of the fourth injection of the rabies vaccine sold in the market; when the antigen contained in the vaccine is injected when the dosage is reduced to one tenth of that of the commercial rabies vaccine, the antibody titer is equivalent to that of the commercial vaccine product. The rabies vaccine delivery system can reduce the times of immunization and can generate stronger immune response on the basis of the same market rabies vaccine single dose unchanged.
Drawings
FIG. 1 shows the result of antibody titer detection after immunization of rabies vaccine delivery system.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of rabies vaccine delivery System
1. Preparation of temperature-sensitive high molecular material solution
PLGA-PEG-PLGA (purchased from biological engineering Co., Ltd. of Jinan Dai Ting et, no commercial product, wherein the molecular weight of PLGA is about 2000, the molecular weight of PEG is about 1500; and phase transition occurs at 30 ℃) is dissolved in normal saline (normal saline is sodium chloride aqueous solution with the concentration of 0.9%) according to the mass volume fraction of 20% (g: ml) at room temperature to obtain PLGA-PEG-PLGA hydrosol (the mass volume ratio of PLGA-PEG-PLGA in the hydrosol is 20%, and the mass volume fraction of 20% means that 20g solute is dissolved in a proper amount of solvent and the volume is fixed to 100 ml).
The specific dissolving method comprises the following steps: adding normal saline into PLGA-PEG-PLGA at room temperature, fully swelling for 24h at 4 ℃, and dissolving for 72h at 10 ℃ and 4 ℃ alternately every 24h (the PLGA-PEG-PLGA copolymer is in a semisolid state, and the PLGA-PEG-PLGA copolymer needs to be dissolved for a long time after being weighed and added with the normal saline), so as to form the freely-flowing hydrosol.
The prepared PLGA-PEG-PLGA hydrosol can not be degraded at the temperature of 4 ℃ for 30-60d or at the temperature of-20 ℃ for one year, and the solution keeps the reversible transformation from sol to gel.
2、Al(OH) 3 Preparation of adjuvant delivery System
Adding 2% mass volume percentage of Al (OH) into PLGA-PEG-PLGA hydrosol prepared in the step 1 3 Adjuvant (unit is g: ml; national reagent Co., Ltd.), and mixing them uniformly with mechanical stirring to give Al (OH) 3 And the mass ratio of PLGA-PEG-PLGA in the system is 1: 10, obtaining the vaccine delivery system with the composite aluminum adjuvant, wherein the phase transition temperature of the system is 30 ℃.
3. Preparation of rabies vaccine temperature-sensitive delivery system
Dissolving rabies vaccine antigen (commercially available rabies vaccine; Liaoning Daozhite stock Co., Ltd.) with physiological saline to obtain 5IU/ml rabies vaccine antigen solution; adding manganese chloride solid into the rabies vaccine antigen solution to obtain a manganese ion-containing rabies vaccine antigen solution, wherein the concentration of the rabies vaccine antigen is 5IU/ml, and the final concentration of manganese chloride is 75.5 mu g/ml;
and (3) adding a manganese ion-containing rabies vaccine antigen solution into the vaccine delivery system of the composite aluminum adjuvant obtained in the step (2), wherein the volume ratio of the vaccine delivery system of the composite aluminum adjuvant to the manganese ion-containing rabies vaccine antigen solution is 1:3, stirring while adding, and uniformly mixing the two under mechanical stirring to obtain the rabies vaccine temperature-sensitive delivery system with the phase transition temperature of 30 ℃.
Wherein, PLGA-PEG-PLGA: al (OH) 3 : rabies vaccine antigen: the proportion of manganese chloride is 150 mg: 15 mg: 3.75 IU: 56.53. mu.g.
Example 2 evaluation of the immune Effect of rabies vaccine delivery System
BALB/C mice were subcutaneously administered to evaluate the immune effect of the rabies vaccine temperature-sensitive delivery system prepared in example 1, and the mice were grouped and administered according to Table 1.
TABLE 1 animal grouping and dosing schedules
The administration dose of the rabies vaccine solution group and the high dose group is 10IU/kg, the low dose group is 1IU/kg, the immunization program of the rabies vaccine solution group is the same as that used in clinic, the immunization is carried out on the 0 th, 3 th, 7 th, 14 th and 28 th days, and the multiple immunization time of the temperature-sensitive delivery system group is respectively as follows: the administration was performed at 0, 14d for 2 immunizations, and at 0, 14, 28d for 3 immunizations.
In the above, the rabies vaccine temperature-sensitive delivery system is prepared without manganese according to the following method:
dissolving rabies vaccine antigen by using normal saline to obtain rabies vaccine antigen solution, and obtaining 5IU/ml rabies vaccine antigen solution; adding a rabies vaccine antigen solution into the vaccine delivery system of the composite aluminum adjuvant obtained in the step 2 of the example 1, wherein the volume ratio of the vaccine delivery system of the composite aluminum adjuvant to the rabies vaccine antigen solution is 1: and 3, stirring while adding, and uniformly mixing the two under mechanical stirring to obtain a rabies vaccine delivery system (without adding manganese ions) with the phase transition temperature of 30 ℃.
After the administration, the antibody titer in the blood is detected by the following specific method:
antibody titer testThe detection method adopts ELISA method, and the collected immune serum is respectively diluted by 10 times and 10 times 2 Multiple, 10 3 10 times of 4 Multiple, 10 5 Double, negative serum was added as a control. Measuring absorbance value by ELISA method (key parameters are that the antigen coating concentration is 3 μ g/hole, the second antibody is goat anti-mouse second antibody (purchased from China fir Jinqiao biological company), the dilution multiple of the second antibody is 5000 times, other steps are same with conventional ELISA detection), and taking absorbance value to meet serum absorbance value after immunization>And (3) recording the light absorption value of the maximum dilution multiple which is more than 2 times of the light absorption value of the negative serum as a reference light absorption value, recording the dilution multiple as a reference dilution multiple, substituting the data into the following formula to calculate the antibody titer, and performing mapping comparison.
Calculating the formula: antibody titer ═ reference absorbance ÷ negative serum absorbance × reference dilution factor
As shown in fig. 1, the amount of antibody produced by the rabies vaccine delivery system group was significantly increased compared to the rabies vaccine solution group alone; the antibody amount generated by the manganese-containing low-dose 3-time administration group is basically equivalent to that generated by the rabies vaccine solution group 14d, and is remarkably higher than that generated by the rabies vaccine solution group after 21d, which indicates that the temperature-sensitive delivery system can reduce the immunization dose and the immunization times and can obtain better immunization effect.
The comparison result of each group added with manganese ions and the group not added with manganese ions shows that each group added with manganese ions has higher antibody titer and better immune effect under the condition that the administration times are 2 times and the dosage is the same; similar immune effect can be obtained by reducing the administration frequency to 1 time and under the condition of the same dosage; the addition of manganese ions can improve the immune response level and reduce the immune frequency.
In conclusion, the temperature-sensitive delivery system can reduce the administration dosage and the administration times of the rabies vaccine, thereby reducing the safety risk caused by multiple injections and reducing the pain of vaccine recipients.
The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.
Claims (3)
1. A method for preparing a rabies vaccine temperature-sensitive delivery system comprises the following steps:
1) preparing a vaccine delivery system of a composite aluminum adjuvant and a rabies vaccine antigen solution containing manganese ions;
the vaccine delivery system of the composite aluminum adjuvant is prepared by mixing PLGA-PEG-PLGA hydrosol and Al (OH) 3 Uniformly mixing the adjuvants to obtain a vaccine delivery system of the composite aluminum adjuvant;
the PLGA-PEG-PLGA hydrosol is obtained by dissolving PLGA-PEG-PLGA in physiological saline to obtain PLGA-PEG-PLGA hydrosol, wherein the PLGA-PEG-PLGA has a mass volume percentage content of 20%;
the Al (OH) 3 The mass percentage to volume percentage content of the adjuvant is 2 percent;
in the vaccine delivery system of the composite aluminum adjuvant, the PLGA-PEG-PLGA hydrosol and Al (OH) 3 The mass ratio of the adjuvant is 10: 1;
the molecular weight of PLGA in the PLGA-PEG-PLGA is 2000, and the molecular weight of PEG is 1500;
the manganese ion-containing rabies vaccine antigen solution is prepared by uniformly mixing a rabies vaccine antigen, manganese chloride and physiological saline to obtain a manganese ion-containing rabies vaccine antigen solution, wherein the final concentration of the rabies vaccine antigen is 5IU/ml, and the final concentration of the manganese chloride is 75.5 mu g/ml;
2) mixing the vaccine delivery system of the composite aluminum adjuvant with the rabies vaccine antigen solution containing the manganese ions to obtain a rabies vaccine temperature-sensitive delivery system;
in the rabies vaccine temperature-sensitive delivery system, the weight ratio of PLGA-PEG-PLGA: the Al (OH) 3 : the rabies vaccine antigen: the proportion of the manganese chloride is 150 mg: 15 mg: 3.75 IU: 56.53. mu.g.
2. A rabies vaccine temperature-sensitive delivery system prepared by the method of claim 1.
3. The use of the rabies vaccine temperature-sensitive delivery system according to claim 2 in the preparation of an immune human or animal product;
or, the application of the rabies vaccine temperature-sensitive delivery system in the preparation of products for preventing and treating rabies;
or, the application of the rabies vaccine temperature-sensitive delivery system in preparing products for improving the titer or content of antibodies generated after immunization of human or animals according to claim 2.
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| CN105188569A (en) * | 2013-03-15 | 2015-12-23 | 考里安国际公司 | Microstructure array for delivery of active agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2823119B1 (en) * | 2001-04-05 | 2004-02-20 | Seppic Sa | IMMUNITY ADJUVANT CONTAINING COMPLEX METAL CATION AND VACCINE CONTAINING SAME |
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| CN1413118A (en) * | 1999-12-22 | 2003-04-23 | 株式会社三养社 | Liquid composition of biodegradable block copolymer for drug delivery system and process for preparation thereof |
| WO2007149802A2 (en) * | 2006-06-19 | 2007-12-27 | 3M Innovative Properties Company | Formulation for delivery of immune response modifiers |
| CN102370978A (en) * | 2010-08-17 | 2012-03-14 | 财团法人工业技术研究院 | Thermosensitive hepatitis B vaccine |
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