CN108379573A - A kind of pertussis vaccine microneedle array and preparation method thereof - Google Patents
A kind of pertussis vaccine microneedle array and preparation method thereof Download PDFInfo
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- CN108379573A CN108379573A CN201810254703.5A CN201810254703A CN108379573A CN 108379573 A CN108379573 A CN 108379573A CN 201810254703 A CN201810254703 A CN 201810254703A CN 108379573 A CN108379573 A CN 108379573A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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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
- A61K39/02—Bacterial antigens
- A61K39/099—Bordetella
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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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
- A61K2039/55511—Organic adjuvants
- A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
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Abstract
The invention discloses a kind of preparation methods of pertussis vaccine microneedle array, include the following steps：1) microneedle array mold is used, the microneedle array mold includes substrate, and upper surface of base plate is provided with rectangular recess, and the bottom wall of rectangular recess is provided with the downward conical socket of array tip；2) by pertussis toxin aqueous solution and adjuvant aqueous solution, mixing obtains solution one, is added in rectangular recess, is stood under vacuum condition, so that solution one is full of conical socket, sucks solution one extra other than conical socket, dry；3) high molecular polymer aqueous solution is smeared into rectangular recess, it is dry, the film with cone-shaped protrusion is deviate from from microneedle array mold, vacuum drying.The method of the present invention obtains pertussis vaccine microneedle array, and dosage is accurate, product specification, safe operation.
Description
Technical field
The invention belongs to vaccine administration device technical field, it particularly relates to a kind of pertussis vaccine microneedle array and
Preparation method.
Background technology
Pertussis is a kind of Acute respiratory infectious disease caused by Bordetella pertussis, generally by pertussis Bao Te bacillus
Caused by (abbreviation Bordetella pertussis) infection, the bronchicanis Bao Te bacillus and parapertussis Bao Te bacillus that belong to can also be drawn
It rises.Pertussis Bao Te bacillus is gram negative bacilli, can generate some morbid substances, including pertussis toxin, tracheal cell poison
Element, adenyl cyclase toxin, heat-labile toxin and endotoxin etc..Pertussis toxin can make the lymph in patient's lymphoid tissue
Cell mobilization to peripheral blood and tracheae, cytotoxin can specific Damage tracheal cilia epithelial cell, be allowed to be denaturalized, necrosis.
Pertussis patient, subclinical infection person and carrier are the infection sources.The latent end of term is most strong to 2~3 weeks after being ill infectiousness.Pertussis passes through
Respiratory tract droplet transmission, 5 years old or less infant influenza highest, after children's vaccine inoculation 10 years, pertussis infection rate be not inoculated with
Person's indistinction.
In general, the convenient administration mode of pertussis vaccine is drug administration by injection, although directly effectively, its object of inoculation
Usually child, since injection system can cause pain and skin injury, and operation difficulty is big, cannot be from use, it will usually
Many difficulties are brought to inoculation.
Microneedle transdermal delivery, can be to avoid disadvantage mentioned above as a kind of new administering mode.The small needle of this micro-meter scale
Epidermis can effectively be pierced through and reach skin corium, and in the case where not touching nervous system, released medicine into vivo,
Complete administration.
But the method for preparing microneedle transdermal delivery at present cannot accomplish accurate measurement.Also not by traditional pertussis vaccine
With the report that micropin medicine-feeding technology is combined.
Invention content
The purpose of the present invention is overcome the deficiencies of the prior art and provide a kind of pertussis vaccine microneedle array.
Second object of the present invention is to provide a kind of preparation method of pertussis vaccine microneedle array.
Technical scheme of the present invention is summarized as follows：
A kind of preparation method of pertussis vaccine microneedle array, includes the following steps：
1) microneedle array mold is used, the microneedle array mold includes substrate (1), is provided in substrate (1) upper surface
Rectangular recess (2) is provided with the downward conical socket of array tip (3) in the bottom wall of rectangular recess (2)；
2) by the adjuvant aqueous solution of the pertussis toxin aqueous solution of 0.1-1mg/ml and a concentration of 0.1-100mg/ml, by body
Product is than being 1:The ratio mixing of 1-10 obtains solution one, is added in rectangular recess (2), stands 10-60min under vacuum condition, make
Solution one is full of conical socket (3), sucks solution one extra other than conical socket (3), dry 30-120min；
3) it is 10%-50% high molecular polymer aqueous solutions that mass concentration is smeared into rectangular recess, 8-12 hours dry,
Film with cone-shaped protrusion is deviate from from microneedle array mold, vacuum drying obtains a kind of pertussis vaccine microneedle array.
Adjuvant is preferably CpG.
High molecular polymer is preferably the polyethylene of molecular weight 10000-100000, and poly- the third of molecular weight 80000-150000
Alkene, the polyvinyl alcohol of viscosity average molecular weigh 16000-200000, the polymethyl acrylate of molecular weight 10000-50000, molecular weight
One or more of polymethyl methacrylate of 80000-200000.
The vacuum drying time is preferably 20-26 hours.
Pertussis vaccine microneedle array prepared by the above method.
Advantages of the present invention：
A kind of preparation method of pertussis vaccine microneedle array of the present invention, using microneedle array mold, the mold due to
Each taper can be made recessed when the solution containing pertussis toxin aqueous solution is added to rectangular recess provided with rectangular recess
The liquid volume added of slot is identical, is stood under by vacuum condition, sucks solution extra other than conical socket (3), and each taper is recessed
Sump volume is fixed, when pertussis toxin concentration of aqueous solution is fixed, and the number of conical socket is fixed, so that it may whole accurately to obtain
The pertussis toxin dosage of a microneedle array；Furthermore it is possible to avoid there is no rectangular recess feelings containing pertussis toxin aqueous solution
The spilling of liquid under condition；In addition, high molecular polymer aqueous solution can be made identical in the interior liquid level height of rectangular recess (2), it is made
Product in homogeneous thickness after high molecular polymer drying.By percutaneous dosing, reaches suitable with injection or even be more preferably immunized
Effect.The method of the present invention obtains pertussis vaccine microneedle array, and dosage is accurate, product specification, safe operation.
Description of the drawings
Fig. 1 is to prepare microneedle array mold vertical section schematic diagram used in a kind of pertussis vaccine microneedle array.
Fig. 2 is a kind of pertussis vaccine microneedle array partial enlargement photo prepared by the method for the present invention.
Fig. 3 is a kind of pertussis vaccine microneedle array and subcutaneous inoculation results contrast of the present invention.
Fig. 4 is that a kind of pertussis vaccine microneedle array immune result of various dose compares.
Specific implementation mode
With reference to specific embodiment, the present invention will be further described, and the following examples are to make this field
Technical staff better understood when the present invention, but is not limited in any way to the present invention.
Pertussis toxin (Pertussis toxin, PTX).
Embodiment 1
A kind of preparation method of pertussis vaccine microneedle array, includes the following steps：
1) microneedle array mold is used, sees that Fig. 1, the microneedle array mold include substrate 1, surface is arranged on substrate 1
There is rectangular recess 2, the bottom wall of rectangular recess 2 is provided with the downward conical socket 3 of 10 × 10 array tips, each conical socket
3 volume is 0.02 μ L, and conical socket total volume is 2ul；
2) by the CpG adjuvant aqueous solutions of the deactivation pertussis toxin aqueous solution of 1mg/mL and a concentration of 10mg/mL, by body
Product is than being 1:1 ratio mixing obtains solution one, absorbs 100 microlitres and is added in rectangular recess 2,15min is stood under vacuum condition,
So that solution one is full of conical socket 3, sucks solution one extra other than conical socket 3, dry 60min；
3) polyvinyl alcohol water solution that mass concentration is 30% viscosity average molecular weigh 20000 is smeared into rectangular recess, it is dry
10 hours, the film with cone-shaped protrusion is deviate from from microneedle array mold, vacuum drying for 24 hours, obtains a kind of pertussis vaccine
Microneedle array, microneedle array partial enlarged view are shown in Fig. 2.
It is 1 μ g, CpG adjuvant, 10 μ g that each pertussis vaccine microneedle array, which is loaded with pertussis toxin amount,.
Experiment 1：
Female Balb/c mouse 12,18-20g are selected, two groups is randomly divided into, 6 of experimental group, embodiment is respectively adopted
1 pertussis vaccine microneedle array intradermal immunization；Control group 6 is used respectively containing 1 μ g, CpG adjuvant of pertussis toxin, 10 μ g
Injection intradermal immunization, two groups are immunized once for every three weeks, are immunized altogether twice, detect antibody water in three weeks, blood sampling in six weeks respectively
It is flat, see that Fig. 3, experimental result are shown：After immune for the first time, experimental group immune effect is substantially better than control group；After second is immune,
The two immune effect is suitable.Illustrate that pertussis vaccine microneedle patch is similar to the immune effect of conventional injection pertussis vaccine, and
Have the characteristics that single immunization is efficient.
Embodiment 2
A kind of preparation method of pertussis vaccine microneedle array, includes the following steps：
1) with 1 step 1) of embodiment；
2) it by the CpG adjuvant aqueous solutions of the deactivation pertussis toxin aqueous solution of 0.1mg/mL and a concentration of 10mg/mL, presses
Volume ratio is 1:1 ratio mixing obtains solution one, absorbs 100 microlitres and is added in rectangular recess 2, is stood under vacuum condition
15min makes solution one be full of conical socket 3, sucks solution one extra other than conical socket 3, dry 60min；
3) with 1 step of embodiment (3).
It is 0.1 μ g, CpG adjuvant, 10 μ g that each pertussis vaccine microneedle array, which is loaded with pertussis toxin amount,.
Embodiment 3
A kind of preparation method of pertussis vaccine microneedle array, includes the following steps：
1) with 1 step 1) of embodiment；
2) it by the CpG adjuvant aqueous solutions of the deactivation pertussis toxin aqueous solution of 0.5mg/mL and a concentration of 10mg/mL, presses
Volume ratio is 1:1 ratio mixing obtains solution one, absorbs 100 microlitres and is added in rectangular recess 2, is stood under vacuum condition
15min makes solution one be full of conical socket 3, sucks solution one extra other than conical socket 3, dry 60min；
3) with 1 step of embodiment (3).
It is 0.5 μ g, CpG adjuvant, 10 μ g that each pertussis vaccine microneedle array, which is loaded with pertussis toxin amount,.
Experiment 2：
Female Balb/c mouse 24,18-20g are selected, are randomly divided into 4 groups, embodiment is respectively adopted in embodiment 1 group 6
1 pertussis vaccine microneedle array intradermal immunization；The pertussis vaccine micropin battle array of embodiment 2 is respectively adopted in embodiment 2 groups 6
Row intradermal immunization；The pertussis vaccine microneedle array intradermal immunization of embodiment 2 is respectively adopted in embodiment 3 groups 6；Blank group 6
Only, the PBS injection intradermal immunizations of pH=7.4.
4 groups are immunized once for every three weeks, immune altogether to detect antibody level twice in three weeks, blood sampling in six weeks respectively, see Fig. 4,
Experimental result shows that after immune for the first time, the immune effect of the micropin of three group various doses of embodiment does not have
Significant difference；After second immune, 0.1 microgram group of low dosage (2 groups of embodiment) immune level decreased significantly, middle high dose group
Immune level is suitable, and middle dose group is slightly above high dose group.Illustrate when the dosage of pertussis vaccine micropin is 0.5 microgram to mouse
Immune effect it is best.
Embodiment 4
A kind of preparation method of pertussis vaccine microneedle array, includes the following steps：
1) microneedle array mold is used, sees that Fig. 1, the microneedle array mold include substrate 1, surface is arranged on substrate 1
There is rectangular recess 2, the bottom wall of rectangular recess 2 is provided with the downward conical socket 3 of 10 × 10 array tips, each conical socket
3 volume is 0.02 μ L, and conical socket total volume is 2ul；
2) it by the CpG adjuvant aqueous solutions of the deactivation pertussis toxin aqueous solution of 1mg/mL and a concentration of 0.1mg/mL, presses
Volume ratio is 1:10 ratio mixing obtains solution one, absorbs 100 microlitres and is added in rectangular recess 2, is stood under vacuum condition
15min makes solution one be full of conical socket 3, sucks solution one extra other than conical socket 3, dry 60min；
3) polyvinyl alcohol water solution that mass concentration is 30% viscosity average molecular weigh 20000 is smeared into rectangular recess, it is dry
10 hours, the film with cone-shaped protrusion is deviate from from microneedle array mold, vacuum drying for 24 hours, obtains a kind of pertussis vaccine
Microneedle array.
It is 0.182 μ g, CpG adjuvant, 0.182 μ g that each pertussis vaccine microneedle array, which is loaded with pertussis toxin amount,.
Embodiment 5
A kind of preparation method of pertussis vaccine microneedle array, includes the following steps：
1) microneedle array mold is used, sees that Fig. 1, the microneedle array mold include substrate 1, surface is arranged on substrate 1
There is rectangular recess 2, the bottom wall of rectangular recess 2 is provided with the downward conical socket 3 of 10 × 10 array tips, each conical socket
3 volume is 0.02 μ L, and conical socket total volume is 2ul；
2) it by the CpG adjuvant aqueous solutions of the deactivation pertussis toxin aqueous solution of 1mg/mL and a concentration of 100mg/mL, presses
Volume ratio is 1:5 ratio mixing obtains solution one, absorbs 100 microlitres and is added in rectangular recess 2, is stood under vacuum condition
10min makes solution one be full of conical socket 3, sucks solution one extra other than conical socket 3, dry 120min；
3) polyvinyl alcohol water solution that mass concentration is 50% viscosity average molecular weigh 16000 is smeared into rectangular recess, it is dry
12 hours, the film with cone-shaped protrusion is deviate from from microneedle array mold, is dried in vacuo 26h, obtains a kind of pertussis vaccine
Microneedle array.
It is 0.33 μ g, CpG adjuvant 166.67 that each pertussis vaccine microneedle array, which is loaded with pertussis toxin amount,.
Embodiment 6
A kind of preparation method of pertussis vaccine microneedle array, includes the following steps：
1) microneedle array mold is used, sees that Fig. 1, the microneedle array mold include substrate 1, surface is arranged on substrate 1
There is rectangular recess 2, the bottom wall of rectangular recess 2 is provided with the downward conical socket 3 of 10 × 10 array tips, each conical socket
3 volume is 0.02 μ L, and conical socket total volume is 2ul；
2) by the CpG adjuvant aqueous solutions of the deactivation pertussis toxin aqueous solution of 1mg/mL and a concentration of 10mg/mL, by body
Product is than being 1:1 ratio mixing obtains solution one, absorbs 100 microlitres and is added in rectangular recess 2,60min is stood under vacuum condition,
So that solution one is full of conical socket 3, sucks solution one extra other than conical socket 3, dry 30min；
3) polyvinyl alcohol water solution that mass concentration is 10% viscosity average molecular weigh 200000 is smeared into rectangular recess, it is dry
8 hours, the film with cone-shaped protrusion is deviate from from microneedle array mold, is dried in vacuo 20h, it is micro- to obtain a kind of pertussis vaccine
Needle array.
It is 1 μ g, CpG adjuvant, 10 μ g that each pertussis vaccine microneedle array, which is loaded with pertussis toxin amount,.
It is demonstrated experimentally that with the polyethylene of molecular weight 10000, the polyethylene of molecular weight 100000, poly- the third of molecular weight 80000
Alkene, the polypropylene of molecular weight 150000, the polymethyl acrylate of molecular weight 10000, the polymethyl acrylate of molecular weight 50000,
In the polymethyl methacrylate of molecular weight 80000 or the polymethyl methacrylate alternate embodiment 1 of molecular weight 200000
The polyvinyl alcohol of average molecular weight 20000, the other the same as in Example 1 respectively obtain pertussis vaccine microneedle array.
Claims (5)
1. a kind of preparation method of pertussis vaccine microneedle array, it is characterized in that including the following steps：
1) microneedle array mold is used, the microneedle array mold includes substrate (1), and substrate (1) upper surface is provided with rectangle
Groove (2) is provided with the downward conical socket of array tip (3) in the bottom wall of rectangular recess (2)；
2) by the adjuvant aqueous solution of the pertussis toxin aqueous solution of 0.1-1mg/ml and a concentration of 0.1-100mg/ml, by volume
It is 1:The ratio mixing of 1-10 obtains solution one, is added in rectangular recess (2), stands 10-60min under vacuum condition, make solution
One is full of conical socket (3), sucks solution one extra other than conical socket (3), dry 30-120min；
3) it is 10%-50% high molecular polymer aqueous solutions that mass concentration is smeared into rectangular recess, 8-12 hours dry, by band
There is the film of cone-shaped protrusion to deviate from from microneedle array mold, vacuum drying obtains a kind of pertussis vaccine microneedle array.
2. according to the method described in claim 1, it is characterized in that the adjuvant is CpG.
3. according to the method described in claim 1, it is characterized in that the high molecular polymer is molecular weight 10000-100000's
Polyethylene, the polypropylene of molecular weight 80000-150000, the polyvinyl alcohol of viscosity average molecular weigh 16000-200000, molecular weight
The polymethyl acrylate of 10000-50000, one or more of the polymethyl methacrylate of molecular weight 80000-200000.
4. according to the method described in claim 1, it is characterized in that the vacuum drying time is 20-26 hours.
5. pertussis vaccine microneedle array prepared by the method for one of claim 1-4.
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2018
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