CN118078764A - Stable human rabies vaccine freeze-dried preparation and preparation method thereof - Google Patents
Stable human rabies vaccine freeze-dried preparation and preparation method thereof Download PDFInfo
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- CN118078764A CN118078764A CN202310278187.0A CN202310278187A CN118078764A CN 118078764 A CN118078764 A CN 118078764A CN 202310278187 A CN202310278187 A CN 202310278187A CN 118078764 A CN118078764 A CN 118078764A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 229960003127 rabies vaccine Drugs 0.000 title claims abstract description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 30
- 239000003381 stabilizer Substances 0.000 claims abstract description 30
- 238000004108 freeze drying Methods 0.000 claims abstract description 27
- 241000711798 Rabies lyssavirus Species 0.000 claims abstract description 17
- 239000000427 antigen Substances 0.000 claims abstract description 15
- 102000036639 antigens Human genes 0.000 claims abstract description 15
- 108091007433 antigens Proteins 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 238000009472 formulation Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 5
- 239000008363 phosphate buffer Substances 0.000 claims abstract 3
- 239000008055 phosphate buffer solution Substances 0.000 claims description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 239000011265 semifinished product Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000004806 packaging method and process Methods 0.000 claims description 8
- 230000001954 sterilising effect Effects 0.000 claims description 8
- 238000004659 sterilization and disinfection Methods 0.000 claims description 8
- 229940119744 dextran 40 Drugs 0.000 claims description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 3
- 102000009027 Albumins Human genes 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 239000012931 lyophilized formulation Substances 0.000 claims 5
- 229960005486 vaccine Drugs 0.000 abstract description 8
- 238000011160 research Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 230000007774 longterm Effects 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 239000003223 protective agent Substances 0.000 abstract description 2
- 230000009466 transformation Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract 1
- 229920001503 Glucan Polymers 0.000 description 14
- 102000008100 Human Serum Albumin Human genes 0.000 description 11
- 108091006905 Human Serum Albumin Proteins 0.000 description 11
- 230000001105 regulatory effect Effects 0.000 description 7
- 206010037742 Rabies Diseases 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000011835 investigation Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000003501 vero cell Anatomy 0.000 description 2
- 206010002515 Animal bite Diseases 0.000 description 1
- 206010043417 Therapeutic response unexpected Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000035472 Zoonoses Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 206010048282 zoonosis Diseases 0.000 description 1
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a stable freeze-dried preparation of rabies vaccine for human and a preparation method thereof. The formulation of the preparation comprises rabies virus antigen, a stabilizer, a freeze-dried excipient and a phosphate buffer. Compared with the prior art, the auxiliary material has simple component composition, no component derived from animal sources and lower risk. The concentration of the protective agent is low, and the vaccine activity loss in the freeze-drying process can be effectively controlled. After the preparation is prepared into a finished product, the finished product has good stability through thermal stability research, accelerated stability research and long-term stability research, has low clinical side reaction and high positive transformation rate, generates antibodies quickly, and protects rights of inoculators.
Description
Technical Field
The invention relates to the technical field of biological products, in particular to a stable freeze-dried preparation of rabies vaccine for human and a preparation method thereof.
Background
Rabies is a zoonotic disease caused by rabies virus, and is widely distributed worldwide, and the number of people dying from rabies per year exceeds 5.5 ten thousand, wherein about 95% of the diseases occur in asia and africa. Most of the death events are caused by dog bites infected with rabies virus, 30% -60% of victims are children under 15 years of age. Rabies is usually prevented and treated by rabies vaccine.
At present, the production of rabies vaccine mainly cultures and harvests rabies virus by culturing Vero cells and proliferating rabies virus on Vero cells, and after purification and inactivation, human serum albumin with a certain concentration is added to prepare various liquid and freeze-dried preparations, so that the rabies vaccine is an immunity vaccine for preventing and treating rabies after exposure, and can effectively stimulate organism to produce anti-rabies virus antibodies clinically and prevent rabies. However, the existing vaccine products have large clinical side effects, low stability and slow antibody production, so that the stable and good-effect human rabies vaccine freeze-dried preparation and the preparation method thereof are technical problems to be solved urgently by the technicians in the field.
Disclosure of Invention
The invention aims to solve the technical problems that: overcomes the defects in the prior art and provides a stable freeze-dried preparation of human rabies vaccine and a preparation method thereof.
In order to solve the problems, the technical scheme provided by the invention is as follows: a stable human rabies vaccine freeze-dried preparation comprises rabies virus antigen, a stabilizer, freeze-dried excipient and phosphate buffer solution.
Preferably, the pH value of the phosphate buffer solution is 7.2-8.0, the phosphate buffer solution is PBS, and the phosphate buffer solution also comprises sodium chloride, wherein the mass concentration of the sodium chloride is 0.85%.
Preferably, the stabilizer is human blood albumin, and the mass concentration is 1% -2%.
Preferably, the freeze-drying excipient is dextran 40, and the mass concentration is 3% -5%.
Preferably, the preparation is bottled, with a specification of 0.5 ml/bottle.
The preparation method of the freeze-dried preparation comprises the following steps:
1) Preparing phosphate buffer solution;
2) Adding a stabilizer human serum albumin, lyophilizing an excipient glucan 40 solution, and regulating the pH of the mixed solution of the stabilizer human serum albumin and the excipient glucan 40 solution;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, and controlling the pH;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine.
Preferably, the pH in the step 2 is 7.2-8.0.
Preferably, the rabies virus antigen in the step 3 has the content of 7.0-13.0IU per milliliter and the pH value of 7.3-7.8.
The beneficial effects of the invention are as follows: (1) The auxiliary materials (human serum albumin, dextran 40, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride) have simple composition, no components derived from animal sources and lower risk. (2) The concentration of the protective agent (human serum albumin) is low, and the vaccine activity loss in the freeze-drying process can be effectively controlled. (3) After the preparation is prepared into a finished product, the finished product shows good stability through thermal stability research, accelerated stability research and long-term stability research. (4) The preparation has low clinical side effect, high positive transformation rate, fast antibody production and protecting the rights of the inoculator after being prepared into a finished product.
Detailed Description
The invention is illustrated but not limited by the following examples. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.
Example 1:
1) Preparing phosphate buffer solution with pH of 7.2-8.0 and sodium chloride mass concentration of 0.85%;
2) Human serum albumin as a stabilizer at a final concentration of 1%; preparing 20% glucan 40 solution as a freeze-drying excipient, wherein the final concentration of glucan 40 is 5%; adjusting the pH value of the mixed solution to 7.2-8.0;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, wherein the content of each milliliter is 7.0IU, and regulating the pH to 7.3-7.8;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine;
5) The bottled formulation had a gauge of 0.5 ml/bottle.
Example 2:
1) Preparing phosphate buffer solution with pH of 7.2-8.0 and sodium chloride mass concentration of 0.85%;
2) Human serum albumin as a stabilizer at a final concentration of 1%; preparing 20% glucan 40 solution as a freeze-drying excipient, wherein the final concentration of glucan 40 is 3%; adjusting the pH value of the mixed solution to 7.2-8.0;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, wherein the content of each milliliter is 9.0IU, and regulating the pH to 7.3-7.8;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine;
5) The bottled formulation had a gauge of 0.5 ml/bottle.
Example 3:
1) Preparing phosphate buffer solution with pH of 7.2-8.0 and sodium chloride mass concentration of 0.85%;
2) Human serum albumin as a stabilizer at a final concentration of 1%; preparing 20% glucan 40 solution as a freeze-drying excipient, wherein the final concentration of glucan 40 is 4%; adjusting the pH value of the mixed solution to 7.2-8.0;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, wherein the content of each milliliter is 13.0IU, and regulating the pH to 7.3-7.8;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine;
5) The bottled formulation had a gauge of 0.5 ml/bottle.
Example 4:
1) Preparing phosphate buffer solution with pH of 7.2-8.0 and sodium chloride mass concentration of 0.85%;
2) Human serum albumin as a stabilizer at a final concentration of 2%; preparing 20% glucan 40 solution as a freeze-drying excipient, wherein the final concentration of glucan 40 is 5%; adjusting the pH value of the mixed solution to 7.2-8.0;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, wherein the content of each milliliter is 7.0IU, and regulating the pH to 7.3-7.8;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine;
5) The bottled formulation had a gauge of 0.5 ml/bottle.
Example 5:
1) Preparing phosphate buffer solution with pH of 7.2-8.0 and sodium chloride mass concentration of 0.85%;
2) Human serum albumin as a stabilizer at a final concentration of 2%; preparing 20% glucan 40 solution as a freeze-drying excipient, wherein the final concentration of glucan 40 is 3%; adjusting the pH value of the mixed solution to 7.2-8.0;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, wherein the content of each milliliter is 9.0IU, and regulating the pH to 7.3-7.8;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine;
5) The bottled formulation had a gauge of 0.5 ml/bottle.
Example 6:
1) Preparing phosphate buffer solution with pH of 7.2-8.0 and sodium chloride mass concentration of 0.85%;
2) Human serum albumin as a stabilizer at a final concentration of 2%; preparing 20% glucan 40 solution as a freeze-drying excipient, wherein the final concentration of glucan 40 is 4%; adjusting the pH value of the mixed solution to 7.2-8.0;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, wherein the content of each milliliter is 13.0IU, and regulating the pH to 7.3-7.8;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine;
5) The bottled formulation had a gauge of 0.5 ml/bottle.
1. Examples 1-6 vaccine antigen content comparison before and after lyophilization
| Examples | Semi-finished product formulation point (IU/ml) | Finished antigen content (IU/ml) |
| 1 | 7.0 | 8.8 |
| 2 | 9.0 | 10.4 |
| 3 | 13.0 | 15.1 |
| 4 | 7.0 | 8.6 |
| 5 | 9.0 | 10.5 |
| 6 | 13.0 | 15.4 |
2. Examples 1 to 6 stability investigation
A. Long term stability results of rabies vaccine
( The investigation condition is 2-8 ℃ for 0-18 months; potency standard 2.5 IU/dose. )
B. Accelerated stability results of rabies vaccine
( The investigation condition is 25+/-2 ℃ for 0-6 months; potency standard 2.5 IU/dose. )
| Study date | 1 | 2 | 3 | 4 | 5 | 6 |
| For 0 month | 4.8 | 6.7 | 7.8 | 5.6 | 6.4 | 7.2 |
| 1 Month | 3.4 | 5.4 | 6.6 | 5.4 | 6.6 | 6.6 |
| 2 Months of | 4.4 | 4.8 | 6.5 | 6.1 | 5.9 | 5.5 |
| For 3 months | 4.2 | 5.6 | 6.3 | 5.2 | 6.0 | 6.0 |
| 6 Months of | 2.7 | 4.8 | 5.0 | 5.0 | 5.2 | 5.8 |
C. Results of thermostability of rabies vaccine
( The investigation condition is 37+/-2 ℃ for 0-91 days; potency standard 2.5 IU/dose. )
| Study date | 1 | 2 | 3 | 4 | 5 | 6 |
| Day 0 | 4.8 | 6.7 | 7.8 | 5.6 | 6.4 | 7.2 |
| For 28 days | 3.7 | 4.4 | 5.4 | 5.0 | 5.7 | 6.4 |
| 49 Days | 2.7 | 3.6 | 5.8 | 4.0 | 5.4 | 6.0 |
| For 70 days | 2.8 | 4.8 | 5.4 | 4.5 | 5.0 | 5.6 |
| 91 Days | 2.6 | 4.9 | 5.6 | 4.6 | 5.3 | 6.2 |
3. Comparison of first dose of pre-immune antibody negative population and 7 days after pre-immune positive conversion rate
The vaccine of example 5 was used as a test group, and the vaccine of the control group was a commercial product, which was a domestic comparison well-known rabies vaccine producer product, and the 5 dose test group indicated the 5-needle inoculation program for the preparation of example 5, the 4 dose test group indicated the 4-needle inoculation program for the preparation of example 5, and the 5 dose control group indicated the 5-needle inoculation program for the purchased control vaccine.
4. Comparison of Pre-immune antibody negative population against GMC and fold increase in 7 days after first dose of immunization
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (8)
1. A stable human rabies vaccine freeze-dried preparation is characterized by comprising rabies virus antigen, a stabilizer, freeze-dried excipient and phosphate buffer solution.
2. The lyophilized formulation according to claim 1, wherein the phosphate buffer has a pH of 7.2-8.0, the phosphate buffer is PBS, and further comprising sodium chloride having a mass concentration of 0.85%.
3. The lyophilized formulation according to claim 1, wherein the stabilizer is human blood albumin with a mass concentration of 1% -2%.
4. The lyophilized formulation according to claim 1, wherein the lyophilization excipient is dextran 40 with a mass concentration of 3% -5%.
5. The lyophilized formulation according to claim 1, wherein the formulation is bottled in a size of 0.5 ml/bottle.
6. The method for preparing a lyophilized formulation according to claim 1, comprising the steps of:
1) Preparing phosphate buffer solution;
2) Adding a stabilizer, lyophilizing the excipient solution, and adjusting the pH of the mixture;
3) Semi-finished product preparation is carried out by using phosphate buffer solution, stabilizing agent and freeze-drying excipient after sterilization and filtration: adding a mixed solution of a stabilizer and an excipient into a phosphate buffer solution, and finally adding purified inactivated rabies virus antigen, and controlling the pH;
4) Mixing completely, packaging into bottles, and freeze-drying by a medicinal vacuum freeze dryer to obtain a stable freeze-dried preparation of human rabies vaccine.
7. The method according to claim 6, wherein the pH in the step2 is 7.2 to 8.0.
8. The method according to claim 6, wherein the rabies virus antigen is contained in the amount of 7.0-13.0iu per ml in step 3, and the ph is 7.3-7.8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310278187.0A CN118078764A (en) | 2023-03-21 | 2023-03-21 | Stable human rabies vaccine freeze-dried preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310278187.0A CN118078764A (en) | 2023-03-21 | 2023-03-21 | Stable human rabies vaccine freeze-dried preparation and preparation method thereof |
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| Publication Number | Publication Date |
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| CN118078764A true CN118078764A (en) | 2024-05-28 |
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| CN202310278187.0A Pending CN118078764A (en) | 2023-03-21 | 2023-03-21 | Stable human rabies vaccine freeze-dried preparation and preparation method thereof |
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- 2023-03-21 CN CN202310278187.0A patent/CN118078764A/en active Pending
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