CN105854010A - Hand-foot-mouth disease vaccine system for needleless injection and application - Google Patents
Hand-foot-mouth disease vaccine system for needleless injection and application Download PDFInfo
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- CN105854010A CN105854010A CN201610308472.2A CN201610308472A CN105854010A CN 105854010 A CN105854010 A CN 105854010A CN 201610308472 A CN201610308472 A CN 201610308472A CN 105854010 A CN105854010 A CN 105854010A
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- Prior art keywords
- vaccine
- foot
- hand
- mouth disease
- needleless
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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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/30—Syringes for injection by jet action, without needle, e.g. for use with replaceable ampoules or carpules
-
- 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
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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
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
The invention discloses a hand-foot-mouth disease vaccine system for needleless injection and application and provides a hand-foot-mouth disease vaccine system for needleless injection, comprising a container filled with a hand-foot-mouth disease vaccine and a readable carrier; the readable carrier records the following content: a needleless injection dose of the hand-foot-mouth disease vaccine is not greater than a standard dose of the hand-foot-mouth disease vaccine. Experiments prove that in the joint application of a needleless injection ampule and a needleless syringe in immunization, the vaccine can produce with a traditional intramuscular injection antigen, the same or higher neutralizing antibody level just through the antigen dose being only part of the usage of the traditional intramuscular injection antigen; it is further shown that needleless immunization means is an ideal means selectable to immunizing hand-foot-mouth disease vaccines.
Description
Technical field
The present invention relates to field of medicaments, especially infectious disease field.More particularly, to Needleless injection hand-foot-mouth disease
Disease vaccine system and application.It is applicable to all kinds of vaccine for hand-foot-mouth disease Vaccination and Immunoprophylaxis.
Background technology
At present, the injection needle that domestic and international commonly used rustless steel is made carries out the injection of medicine or vaccine to human body.Many
Well known, the injection of syringe needle can bring such as: medical personnel's accidental puncture, inoculator fear pin and pain and the dirt that intersects
Dye equivalent risk.Therefore, the safety of injection has become the focus problem of clinical manipulation.Also promoted can replace passing
System has the birth needleless note of pin injection system the new drug injection that can avoid above-mentioned harm or vaccination mode
Penetrate mode.Because avoiding the use of syringe needle, the probably pin sense of inoculator particularly child can be overcome, effectively reduce medical care simultaneously
The risk of personnel's needle sting, and the generation of cross-contamination that the improper use of syringe needle causes can be avoided.In recent years, needleless
Injection technique is in the stage of developing rapidly, big with traditional high pressure Needleless injection wound, develops into low pressure needleless note today
Penetrate wound little, promote needleless injection techniques development and application.Because of its prominent advantage its will in medical and health care system
Have the field of being widely applied and unlimited prospect.
Hand-foot-mouth disease is caused by Picornaviridae, enterovirus genus virus, to infantile health and public health
The infectious disease of safe great threat.Since two thousand, China and Asia all occur in that repeatedly hand foot and mouth disease
Large-scale outbreak popular, ten hundreds of child's life and healths is caused grave danger.Hand-foot-mouth disease can be by COxsackie
Virus A4, the enterovirus of the type such as A5, A9, A10, B2, B5 and Enterovirus 71 causes, but main by enterovirus
71 types (EV71) and Coxsackie virus 16 type (Cox.A16) cause.Owing to this disease also lacks effective spy in treatment
Specific agent, vaccination is prevention and the fundamental means controlling this kind of Disease code.EV71 vaccine is in 2015
The approval of acquisition state food pharmaceuticals administration first at year end general bureau, formally put goods on the market use for 2016.This vaccine can
Effectively reduce the hand-foot-mouth disease that EV71 causes, especially reduce serious symptom and the death of hand-foot-mouth disease, to protection China
Children's health is significant.
Use of currently available vaccines, existing vaccines inoculation has pin muscle or subcutaneous location immunity more, there is antigen consumption big, immunne response with
The potential realistic problem that immunoprotection is not enough and side effect is big.The immunogenicity that many researchs it turned out skin is better than flesh
Meat or other approach, medicine or vaccine enter corium, the antigen presenting cell identification enriched by skin corium through horny layer
And capture, and by antigen presentation to T cell, cause immunne response.Needleless injection makes medicine or vaccine noting simultaneously
Penetrate position and present the distribution of netted dispersity, add and the contacting of antigen presenting cell, improve immune response.
Therefore, needleless intradermal injection only needs the Fractional of intramuscular injection can cause identical or higher immunoreation.This is not
Only save vaccine consumption and cost, be protected from the restriction of vaccine shortage, reduce the expense of publilc health economically,
And adverse reaction rate can be reduced.Meanwhile, because Needleless injection can accurately carry out the injection of the different skin degree of depth, improve
Considerably increasing injection efficiency while injection accuracy, also providing for large-scale inoculation may.
Summary of the invention
It is an object of the present invention to provide Needleless injection vaccine for hand-foot-mouth disease system.
The Needleless injection vaccine for hand-foot-mouth disease system that the present invention provides, for following 1) or 2):
1) system shown in includes the container being filled with vaccine for hand-foot-mouth disease, and the fill dosage of described vaccine for hand-foot-mouth disease is little
In the standard dose equal to this vaccine for hand-foot-mouth disease；Wherein, the container being filled with vaccine for hand-foot-mouth disease is single use
The container equipped with vaccine for hand-foot-mouth disease；
2) system shown in includes the container of fill vaccine for hand-foot-mouth disease and readable carrier；Described readable carrier contents
Including: the Needleless injection dosage of described vaccine for hand-foot-mouth disease is less than or equal to this vaccine for hand-foot-mouth disease standard dose；Wherein,
The container being filled with vaccine for hand-foot-mouth disease is the container equipped with vaccine for hand-foot-mouth disease that can use the most continuously.
In said system, vaccine for hand-foot-mouth disease standard dose is for listing vaccine (enterovirns type 71 inactivated vaccine (people
Diploid cell)) the vaccine for hand-foot-mouth disease intramuscular injection dosage announced, in an embodiment of the present invention, hand-foot-mouth disease epidemic disease
Seedling standard dose is that NAT is more than or equal to 3.0EU.
In said system,
The standard dose that fill dosage is 1/3-1 times of this vaccine for hand-foot-mouth disease of described vaccine for hand-foot-mouth disease；
The Needleless injection dosage of described vaccine for hand-foot-mouth disease is 1/3-1 times of this vaccine for hand-foot-mouth disease standard dose.
The standard dose that fill dosage is 1/3-2/3 times of this vaccine for hand-foot-mouth disease of described vaccine for hand-foot-mouth disease；
The Needleless injection dosage of described vaccine for hand-foot-mouth disease is 1/3-2/3 times of this vaccine for hand-foot-mouth disease standard dose.
In said system, the fill dosage of described vaccine for hand-foot-mouth disease or Needleless injection dosage are not more than 3.0EU, and not
It is 0.
And/or, fill dosage or the Needleless injection dosage of described vaccine for hand-foot-mouth disease are specially 1.0EU-3.0EU.
And/or, fill dosage or the Needleless injection dosage of described vaccine for hand-foot-mouth disease are specially 1.0EU or 2.0EU.
In said system, described vaccine for hand-foot-mouth disease is inactivated vaccine, attenuated live vaccine, restructuring VLP vaccine, gene
Any one of engineered vaccine, synthetic peptide, DNA vaccination etc. or several mixing, but it is not limited to this.
In said system, 1) system or 2 shown in) shown in system the most also include being filled with hand-foot-mouth disease epidemic disease with described
The matching used Needleless injection device of container of Seedling；
And/or, described Needleless injection device is specially needleless injector.Above-mentioned needleless injector is Jiangsu Mitt USA Corporation
Needleless injector is (such as: MG-0.1；MP-0.1), the present embodiment is MP-0.1.
Strain included in each embodiment of the present invention or technical scheme is through inactivation and/or purified.
Described inactivation is realized by beta-propiolactone and/or formaldehyde.Purification can pass through clarification filtration, ultrafiltration concentration, from
The method such as the heart and/or chromatography is carried out.
" adjuvant " described in literary composition is the immunogenic material for strengthening vaccine of the present invention or medicament, and giving adjuvant can
Immunne response with enhancing body.Concrete, adjuvant is to known in those skilled in the art.More specifically, assistant
Agent includes but not limited to: Alum adjuvant, such as aluminium hydroxide, aluminum phosphate, aluminum sulfate etc.；Oil-in-water adjuvant, example
Such as MF59, SAF, RiBi adjuvant system etc.；Saponins adjuvant, the such as fat of ISCOMs, bacteria lipopolysaccharide, synthesis
Class A analog or its derivant, analog etc.；Cytokine, such as interleukin, interferon, granulocyte, huge
Phagocyte colony stimulating factor, tumor necrosis factor etc.；And can be as the active substance etc. of immunostimulant.
The dosage form of above-mentioned vaccine is liquid, lyophilized preparation, powder, butterfat or the vaccine system utilizing biodegradation material to embed
Agent etc., but it is not limited to this.
In said system, described in be filled with the container of vaccine for hand-foot-mouth disease be the needle-free injection ampoule being filled with vaccine, its
Including:
One body of pre-fill vaccine,
It is integrally formed at a needleless injector joint of described body one end,
In being slidably arranged in described body by the described body other end and close a power push-rod of described body,
It is arranged on the jet in described needleless injector joint,
It is connected to an arresting lever of the front end of described power push-rod easily brokenly,
It is removably disposed on described needleless injector joint and closes a sealing cap of described jet, and
Be removably disposed on described power push-rod and with a sealing lock dog of the entrance tabling of described body；
Wherein, described jet has a locking groove, and described jet is by described locking groove and described tube cavity phase
Connection；Described arresting lever matches with described locking groove.
In said system, the diameter of described power push-rod is consistent with the internal diameter of described body；Described arresting lever and locking groove
For taper；Described sealing cap uses embedded structure to be removably disposed on described needleless injector joint；
Being provided with sealing lock dog groove on described power push-rod, described sealing lock dog is entrenched in described sealing lock dog groove,
Thus be removably mounted on described power push-rod；
Described sealing cap uses embedded structure to be removably disposed on described needleless injector joint；Described power push-rod
On be provided with sealing lock dog groove, described sealing lock dog is entrenched in described sealing lock dog groove, thus removably pacifies
It is contained on described power push-rod；
Described body, needleless injector joint, jet and locking groove is integrally manufactured forms.
Described body, needleless injector joint, power push-rod, jet and arresting lever all use high-quality medical grade material
Make, such as one or more in glass, polyethylene, polypropylene, Merlon, COP or cyclic polyolefin etc.
Mixing is fabricated by, or by copolymerization, be grafted, the chemical modification such as crosslinking and/or be blended, the physical modification such as filling is carried out
The material optimized, but it is not limited to this.
The a length of 1.5-4cm of above-mentioned tubular body, a length of 0.5-2cm of described needleless injector joint, described power
The a length of 1.5-6cm of push rod, a length of 2-6cm of whole needle-free injection ampoule；Described jet a diameter of
0.05-0.25mm。
In said system, the fill volume of described vaccine for hand-foot-mouth disease is 0.05-1ml；
Or the fill volume of described vaccine is specially 0.1ml or 0.2ml or 0.5ml.
In said system, 2), in the system shown in, described readable carrier contents also includes described hand-foot-mouth disease epidemic disease
The needleless note of the Needleless injection position of Seedling, the Needleless injection mode of described vaccine for hand-foot-mouth disease and described vaccine for hand-foot-mouth disease
Penetrate use volume；
Described Needleless injection position is Intradermal, subcutaneously or intramuscularly；Described Needleless injection position is specially Intradermal.
It is 0.05-0.5ml that the Needleless injection of described vaccine for hand-foot-mouth disease is intended for single use volume；Or described vaccine for hand-foot-mouth disease
Needleless injection be intended for single use volume and be specially 0.1ml or 0.2ml or 0.5ml.
Described Needleless injection mode is continuous immunity or single immunization.
Continuous several times immunity is that repeatedly or bull (only) is immune for a pipe vaccine, can set same dose the most immune, or
Set various dose the most immune.
Said system application in preparation immune animal or people's product is also the scope of protection of the invention；
In above-mentioned application, described animal is specially domestic animal, and described domestic animal is especially specially pig or monkey.
The present invention also protects a kind of to animal or the method for people's immunity vaccine for hand-foot-mouth disease, for carrying out immunity by said system,
Immunizing dose is the Needleless injection dosage in said system.
In said method, immunization ways is specially repeatedly continuous immunity or single immunization；Immunity position be specially Intradermal,
Subcutaneously or intramuscularly.
The vaccine of the present invention can deliver with single dose immunization regimen.Or, the vaccine of the present invention also can be as primary immune
The elementary cell of the scheme of-booster immunization delivers.Or, the vaccine of the present invention can repeatedly deliver by immunization ways.
Immunogenic it is characterized as, relevant to vaccine administration, it is possible to stimulate body to form special neutralizing antibody, or thorn
Swash specific immunocyte, make activated immune cell, breed, break up, finally produce immunological effect.
The feature of safety is, the limitation of the side effect relevant to vaccine administration, especially injection site is through Needleless injection
Reaction after equipment injection alleviates or lacks.
It is that epidermis and skin corium are rich in Langerhans cell and DC cell, and percutaneous is exempted from that skin produces the basis of immunne response
The antigen of epidemic disease is captured by these antigen presenting cells, is transferred to lymph node, thus triggers the activation of T, B cell.Not by
The antigen of capture also can Direct Transfer to lymph node, then by DC cell capture and be presented to lymphocyte.
The experiment proves that the Needleless injection vaccine for hand-foot-mouth disease system that the present invention provides has pin without tradition
Inoculation approach, it is possible to accurately, quickly, painlessly by vaccine inject target area by needleless injector, more
Body is that the approach that need not heavy dose of antigen uses vaccine, and the needle-free injection ampoule of this Needleless injection vaccine can prevent secondary
Utilizing, it is to avoid the generation of cross-contamination, the pre-fill of vaccine before immunity, improve injection speed, accurate immunizing dose is also
Extensive tachysynthesis inoculation provides may.
The immunization ways of the Needleless injection vaccine for hand-foot-mouth disease system of the present invention is a kind of novel immunization strategy, by warp
The immunization route of skin, only needs tradition to have 2/3,1/3 or lower dosage of pin intramuscular injection dosage, gets final product induction of antibodies
Produce and the immune effect of general immunity response；Make simultaneously, it is to avoid the immunization ways of syringe needle also has the advantage that 1)
With safe and simple, quick, and it is applicable to mass immunization；2) reduce injection pain sense, improve injection
Compliance, is particularly well-suited to child and waits the injection of probably pin crowd；3) syringe needle is avoided to abuse the cross-contamination brought；4)
Reduce antigen consumption, reduce side reaction odds, reduce production cost.
Present invention demonstrates Needleless injection vaccine and needle-free injection ampoule when carrying out immunity with needleless injector use in conjunction,
The accuracy of injection and safety.Combination product is improving Immune efficiency, while saving immunization time, on a large scale
Tachysynthesis inoculation provides possibility.
It is also an advantage of the present invention that, when needle-free injection ampoule and needleless injector use in conjunction carry out immunity, antigen is used
Amount only needs a part for conventional intramuscular injections of antigens consumption, can produce same or higher immune effect with it.Enter one
Step explanation needleless immunization ways is the immunity alternative ideal strategy of vaccine for hand-foot-mouth disease.
Accompanying drawing explanation
Fig. 1 is disposable needle-free injection ampoule structural representation.
Fig. 2 is the Needleless injection system being filled with prepared Chinese ink in application system, notes in mice, rat, rabbit skin
Penetrate the photo of prepared Chinese ink distribution.
Fig. 3 is Draize scale standards of grading.
Fig. 4 is DRAIZE scoring after Rhesus Macacus application Needleless injection vaccine for hand-foot-mouth disease systemic injection.
Fig. 5 is DRAIZE scoring after small-sized bar horse pig application Needleless injection vaccine for hand-foot-mouth disease systemic injection.
Detailed description of the invention
Experimental technique used in following embodiment if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, the most commercially obtain.
The description below is that the example of the present invention illustrates in time, but does not means that and be therefore so limited, and every present invention is answering
May be to wherein one or more of the advantage realized in the simple transformation of structure and/or some embodiments during with
All in the protection domain of the application.
Embodiment 1, the preparation of needle-free injection ampoule
With embodiment, the present invention is described in detail below in conjunction with the accompanying drawings.
As shown in Figure 1A, Figure 1B, what the present invention provided pre-installs vaccine or the needle-free injection ampoule of medicine, and it includes one
Body 1, one needleless injector joint 2, power push-rod 3, jet 4, arresting lever 5, seals cap 6
Lock dog 7 is sealed with one；Wherein, body 1 fixes vaccine or the medicine of exact dose, needleless injector for pre-fill
Joint 2 is integrally formed at one end of body 1, and power push-rod 3 is slidably arranged in body 1 by the other end of body 1,
And closed tube 1；Jet 4 is arranged in needleless injector joint 2, and it has a locking groove 8, jet 4
By locking groove 8 and body 1 intracavity inter-connection；Arresting lever 5 is connected to the front end of power push-rod 3 easily brokenly, and stops
Lever 5 matches with locking groove 8.When power push-rod 3 moves forward to bottom body 1, by vaccine from jet 4
During release, arresting lever 5 coincide with locking groove 8, and arresting lever 5 disconnects with power push-rod 3, and rests on stop
In groove 8, thus prevent the recycling of needle-free injection ampoule.Sealing cap 6 is removably disposed in needleless injector and connects
On 2, and close jet 4, seal lock dog 7 and be removably disposed on power push-rod 3, and with body 1
Entrance tabling；After the vaccine or medicine of body 1 fill exact dose, sealing lock dog 7 is installed on power
In the sealing lock dog groove 9 of push rod 3, install on needleless injector joint 2 simultaneously and seal cap 6, sky can be avoided
Gas, antibacterial etc. and vaccine or drug contact, reach sterility requirements, it is also possible to prevents unexpected touching from causing power push-rod to move
The dynamic medicine spilling brought, beneficially vaccine or the long-time storage of medicine and transport.
In above-described embodiment, seal cap 6 and use embedded structure to be removably disposed on needleless injector joint 2；Dynamic
Try hard to recommend and on bar 3, be provided with sealing lock dog groove 9, seal lock dog 7 and be entrenched in sealing lock dog groove 9, thus removable
It is arranged on unloading on power push-rod 3.
In above-described embodiment, the diameter of power push-rod 3 is consistent with the internal diameter of body 1.
In above-described embodiment, arresting lever 5 and locking groove 8 are taper.
In above-described embodiment, a length of 1.5-4cm of body 1, a length of 0.5-2cm of needleless injector joint 2,
The a length of 1.5-6cm of power push-rod 3, a length of 2-6cm of whole needle-free injection ampoule；Jet 4 a diameter of
0.05-0.25mm。
In above-described embodiment, in body 1, the vaccine dose of pre-fill is 0.02-1.0ml.
In above-described embodiment, body 1, needleless injector joint 2, power push-rod 3, jet 4 and arresting lever 5 are equal
Use have good transparency, higher toughness and rigidity, high temperature resistant, hinder wet good with vaccine or the medicine compatibility
High-quality medical grade material is made, such as glass, polyethylene, polypropylene, Merlon, COP (Cyclo olefin polymer,
Cyclic olefin polymer, a kind of optical plastic material), cyclic polyolefin or by copolymerization, be grafted, the chemical modification such as crosslinking
And/or be blended, material that the physical modification such as filling is optimized.
In above-described embodiment, body 1, needleless injector joint 2, jet 4 and locking groove 8 is integrally manufactured forms,
Intensity is high, is simple to manufacture conveniently.
In above-described embodiment, need to carry out sterilizing in the assembling process of the pre-fill of vaccine or medicine and needle-free injection ampoule,
Assembling and the packaging of the needle-free injection ampoule of prepackage vaccine or medicine are all carried out under aseptic environment, detectable substance simultaneously
Reason, chemistry and biological property, and need to check through particulate matter etc..
During needle-free injection ampoule application, as shown in Figure 1B, first the needleless of original prepackage vaccine or medicine is noted
The sealing lock dog 7 penetrating ampoule dismantles separation, by needleless injector joint 2 and needleless injector from power push-rod 3
Connect, then sealing cap 6 is taken off, then the Needleless injection system after combination is resisted against on patient skin location；Open
Dynamic needleless injector, the power set of needleless injector drive the power push-rod 3 of needle-free injection ampoule relative to body 1
Move to bottom body 1, promote the vaccine in body 1 to discharge from jet 4, by antigen (vaccine) accurately, soon
Speed, be painlessly distributed in the positions such as the Intradermal of targeting, subcutaneous, muscle and mucosa, can cause be equivalent to tradition syringe needle note
Penetrate the immunity of organism protected effect that the full doses of antigen of immunity is reached.Now, the arresting lever 5 being connected with power push-rod 3
Inserting in locking groove 6, jet 4 is blocked on top, and disconnects with power push-rod 3；Arresting lever 5 only rests on
In dynamic groove 8, prevent secondary from taking out medicine, the ampoule that secondary inoculation must more renew, thus prevent the weight of needle-free injection ampoule
Multiple utilization.
The various embodiments described above are merely to illustrate the present invention, the structure of the most each parts, arrange position and connected mode etc. thereof
All can be varied from, every equivalents carried out on the basis of technical solution of the present invention and improvement, the most not
Should get rid of outside protection scope of the present invention.
Embodiment 2, Needleless injection vaccine for hand-foot-mouth disease systematic difference
The Needleless injection vaccine for hand-foot-mouth disease system of the present embodiment includes the nothing being filled with 1.0-3.0EU vaccine for hand-foot-mouth disease
Pin injection ampoule and matching used needleless injector.
One, the injection depth of Needleless injection vaccine for hand-foot-mouth disease system is groped
Prepared Chinese ink aqueous solution replacement vaccine is filled to needle-free injection ampoule prepared by embodiment 1, obtains being filled with prepared Chinese ink water
The needle-free injection ampoule of solution.
Prepared Chinese ink aqueous solution be by common be the membrane filtration of 0.22um with black-and-blue ink aperture, collect filtrate and use again
Water for injection dilution obtains the prepared Chinese ink aqueous solution that concentration is 1%.
Needle-free injection ampoule and MIT needleless injector (the Jiangsu assistant officer space rice spy doctor of 0.1ml prepared Chinese ink aqueous solution will be filled with
Treat Science and Technology Ltd., product type: MP-0.1, MG-0.1) connect, obtain Needleless injection device；By Needleless injection
Device is applied to the SD rat between Balb/c mice and the 200-250g between body weight 16-18g and 2.5kg respectively
Rabbit, by position to be injected shaving, every injection 0.1ml prepared Chinese ink aqueous solution.Injection application position is the back of the body of mice
Portion and rat, the big leg outer side of rabbit.
Inject latter 30 minutes, put to death Balb/c mice, SD rat and rabbit, draw at injection site skin with scalpel
Open 2cm2And skin is separated with muscle, carry out liquid distribution position and the degree of depth is observed.
Result as in figure 2 it is shown, A, B be Balb/c mice through needleless intradermal injection, C, D are that SD rat is through needleless skin
Interior injection, E, F are that rabbit is through needleless intradermal injection；It can be seen that only find prepared Chinese ink in dermal zone, not subcutaneous
Region finds prepared Chinese ink, in muscle region, does not finds prepared Chinese ink.Therefore the present invention use Needleless injection vaccine ampoule and
Its supporting liquid to be injected can be by liquid infusion in epidermis, and no liquid is injected in muscle sites.
Two, the preparation of Needleless injection vaccine for hand-foot-mouth disease system
Needleless injection vaccine for hand-foot-mouth disease system include being filled with the vaccine for hand-foot-mouth disease of various dose needle-free injection ampoule,
MIT needleless injector (Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1) and saying
Bright book；
It is filled with the needle-free injection ampoule of vaccine for hand-foot-mouth disease of various dose for being filled with 1.0EU-3.0EU hand-foot-mouth disease
The container of vaccine.
It is 1.0EU-3.0EU that description records the Needleless injection dosage of vaccine for hand-foot-mouth disease, and Needleless injection position is specially
Intradermal, subcutaneously or intramuscularly, Needleless injection mode is single immunization or continuous immunity.
1, the acquisition of vaccine for hand-foot-mouth disease
For vaccine or the medicament of the present invention, can be prepared by the following method, described method includes: by different genes
The virus of type is seeded to the cell cultivated respectively, such as: human diploid cell, vero cell, RD cell etc., continues
The continuous cell cultivating inoculation, after obtain univalent vaccine stock solution through inactivation and purification.Assistant can be added to this vaccinogen liquid
Agent or be added without adjuvant, thus obtain the univalent vaccine for hand-foot-mouth disease or medicament.The univalent vaccine stock solution obtained can
To obtain polyvalent vaccine or medicament through configuration.Described polyvalent vaccine can add adjuvant or without adjuvant.
Concrete, the vaccine of the present invention or medicament can step be prepared by the following method: by cell (human diploid cell,
Vero cell, RD cell etc.) it is enlarged cultivating modes such as () rolling bottle, cell factory, fermentation tanks, train at cell
Support to (those skilled in the art can be determined cell concentration according to actual needs) during some, according to certain ratio
Example (such as: 1-100000MOI) virus inoculation, continues to cultivate (cultivating 2-10 day for 30-40 DEG C) afterwards；Aseptic
Under the conditions of, the monovalent virus liquid after results cultivation；The monovalent virus liquid of results is inactivated (appropriate by adding
Beta-propiolactone or formaldehyde etc.) and purification.The univalent vaccine stock solution obtained can obtain polyvalent vaccine or medicine through configuration
Agent.Described unit price or polyvalent vaccine can add adjuvant or without adjuvant.
Or the vaccine of the present invention is also purchased from Beijing Kexing Biotech Products Co., Ltd, trade name: benefit good fortune since then
Enterovirns type 71 inactivated vaccine (Vero) cell of/Inlive.
Vaccine for hand-foot-mouth disease standard dose is the intramuscular injection dosage described in the description being purchased from, specially 3.0EU.
2, the needle-free injection ampoule of the vaccine for hand-foot-mouth disease of various dose it is filled with
The disposable needle-free injection ampoule of the vaccine for hand-foot-mouth disease being filled with various dose is following three kinds:
Being filled with the disposable needle-free injection ampoule that dosage is 1.0EU vaccine for hand-foot-mouth disease, fill cumulative volume is 0.1ml；
Being filled with the needle-free injection ampoule that dosage is 2.0EU vaccine for hand-foot-mouth disease, wherein vaccine for hand-foot-mouth disease is according to above-mentioned
Configuration mode fill cumulative volume is 0.2ml；
Being filled with the needle-free injection ampoule that dosage is 3.0EU vaccine for hand-foot-mouth disease, wherein vaccine for hand-foot-mouth disease is according to above-mentioned
Configuration mode fill cumulative volume is 0.5ml；
Respectively by the above-mentioned 3 kinds disposable needle-free injection ampoule being filled with vaccine for hand-foot-mouth disease and needleless injector during use
(Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1) connects.
Three, Needleless injection vaccine for hand-foot-mouth disease systematic difference
Needleless injection vaccine for hand-foot-mouth disease system can carry out the vaccine injection of the different parts such as Intradermal, subcutaneous, muscle.
A, 1, immunity
39 body weight are divided at random at the Female Rhesus Monkey (purchased from Military Medical Science Institute's Experimental Animal Center) of 2.5-3kg
For group 1, group 2, group 3, group 4, often group 9；PBS group 3；Group 1, group 2, group 3, group 4 are entered again one
Step is divided into a, tri-groups of b, c, often 3 Rhesus Macacus of group；The dosage that a, b, c are tri-groups is respectively above-mentioned two systems of 1.0EU
The vaccine for hand-foot-mouth disease of above-mentioned two preparations of standby vaccine for hand-foot-mouth disease, 2.0EU, the hand-foot-mouth disease of above-mentioned two preparations of 3.0EU
Vaccine；
Group 1: use the above-mentioned needle-free injection ampoule being filled with 1.0EU, 2.0EU, 3.0EU vaccine for hand-foot-mouth disease respectively
With needleless injector (Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1), carry out
Immunity, carried out intradermal immunization at the 0th, 28 days, and immunization ways is with the volume of every dose of 0.1ml (can multi-point injection)
It is applied in thigh exterior lateral area, named needleless Intradermal 1.0EU, needleless Intradermal 2.0EU, needleless Intradermal 3.0EU.
Group 2: use the above-mentioned needle-free injection ampoule being filled with 1.0EU, 2.0EU, 3.0EU vaccine for hand-foot-mouth disease respectively
With needleless injector (Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1), carry out
Immunity, carried out subcutaneous inoculation at the 0th, 28 days, and immunization ways is with the volume of every dose of 0.1ml (can multi-point injection)
It is applied in thigh exterior lateral area, named needlefree 1.0EU, needlefree 2.0EU, needlefree 3.0EU.
Group 3: use the above-mentioned needle-free injection ampoule being filled with 1.0EU, 2.0EU, 3.0EU vaccine for hand-foot-mouth disease respectively
With needleless injector (Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1), carry out
Immunity, carried out intramuscular immunisation at the 0th, 28 days, and immunization ways is to be applied to big leg outer side with the volume of every dose of 0.5ml
In region, named needleless muscle 1.0EU, needleless muscle 2.0EU, needleless muscle 3.0EU.
Group 4: the needle injection that has using tradition 0.5mm*20mm to be specification carries out immunity, enters respectively at the 0th, 28 days
The vaccine for hand-foot-mouth disease of above-mentioned two preparations of row intramuscular immunisation 1.0EU, 2.0EU, 3.0EU, immunization ways is with every dose of 0.5ml
Volume be applied in thigh exterior lateral area, named have pin 1.0EU, have pin 2.0EU, have pin 3.0EU.
PBS group: the needle injection that has using tradition 0.5mm*20mm to be specification is injected, at the 0th, 28 days respectively
Carrying out intramuscular injection PBS, immunization ways is to be applied in thigh exterior lateral area with the volume of every dose of 0.5ml, named
PBS control group.
2, NAT measures
Within 14 days after each treated animal Full-access immunization, collect serum, use microneutralization test method to measure in the EV71 of serum
And antibody titer.Specifically:
(1) being inactivated 30 minutes by test serum 56 DEG C, take one piece of 96 orifice plate and laterally use, every block of plate can do 6 parts
Test serum, carries out serial dilution to serum to be checked.The 96 every holes of orifice plate add 50 μ l diluents；A1-A12: every hole
Adding respective sample 50 μ l, A row inhale 50 μ l to B row mixings after mixing, mixing is diluted to G row successively, inhales
The antibody 50 μ l taking G row discards；H1-H6 adds corresponding test serum sample 50 μ l, mixing；Cell control well
Add antibody diluent (199 culture medium containing 2% hyclone) 50 μ l, mixing；
(2) by EV71 virus (human enterovirus 71, H-9 strain, the common micro-life of China Committee for Culture Collection of Microorganisms
Thing center registration label CGMCC3650) it is diluted to 100CCID50/ 0.05ml, takes the 50 vertical hanging drops of μ l and enters 96 orifice plate (blood
Clearly, except cell controls) each hole in；Separately take 1.5ml 100CCID50/ 0.05ml is viral in little centrifuge tube, 4 DEG C
Temporary, treat back to survey virus titer；
(3) Tissue Culture Plate is patted mixing, to 37 DEG C of 5%CO2With 2 hours in incubator；
(4) virus titer returns and measures 3 tubules, and often pipe adds 0.9ml diluent, draws 0.1ml 100
CCID50/ 0.05ml virus adds in the 1st pipe, as 10CCID after mixing50/ 0.05ml, 10 times are diluted to successively
0.1CCID50/0.05ml；Separately take one 96 orifice plates, each every hole of dilution virus is added 0.1ml, and does 8
Multiple hole；Reserving 4 holes as cell control well, every hole adds 0.1ml viral dilution liquid simultaneously；
(5) use Digestive system peptic cell, be prepared as 2 × 105The vero cell of individual/ml (purchased from ATCC CCL-81,
Use generation: 135-150) suspension, every hole is separately added into 0.1ml cell suspension, mixing, puts into 37 DEG C of 5%CO2
Incubator is hatched cultivation；Observe with microscope, when cultivating to when vero cytopathy is not further added by plate, use Reed
&Muench method calculates in antiserum and titer.
Result such as table 1, for the level of different group rhesus serum neutralizing antibodies, it can be seen that through intradermal injection
The NAT of 1.0EU, 2.0EU, 3.0EU Needleless injection vaccine for hand-foot-mouth disease systemic vaccination and tradition have pin flesh
The antibody titer of meat injection 3.0EU maintains an equal level；Equally, through subcutaneous, intramuscular injection 3.0EU Needleless injection hand-foot-mouth disease epidemic disease
The NAT of Seedling systemic vaccination also has the antibody titer of pin intramuscular injection 3.0EU to maintain an equal level with tradition.This result table
The Needleless injection vaccine for hand-foot-mouth disease system of bright low dose can produce through intradermal immunization has pin to inject phase with standard dose muscle
Same neutralizing antibody level.Meanwhile, this Needleless injection vaccine for hand-foot-mouth disease system also can swash through subcutaneous, intramuscular injection
Send out body and produce identical NAT.
NAT after table 1 Rhesus Macacus immunity
3, systemic immunity safety evaluatio DRAIZE scoring
In after application Needleless injection vaccine for hand-foot-mouth disease systemic immunity Rhesus Macacus 5 days, every day observes injection site
Skin injury situation.And mark according to degree of impairment and degree.Standards of grading are as shown in Figure 3.0 point: do not have
Erythema, has no edema；1 point: slight erythema, skin has slight protuberance, is almost difficult to discover；2 points: clear erythema,
It can be seen that significantly swell；3 points: moderate erythema, the visible limbus of protuberance；4 points: severe erythema, and have incrustation
And deep lesions.In Fig. 4 represents immunity latter 5 days, the degree of impairment of injection site skin is marked and is tied by each injection system
Really, needleless intramuscular injection is similar to there being pin intramuscular injection DRAIZE appraisal result, the 1st day and the 2nd the most after injection
There is accidental excoriation and slight erythema in it.And the 4th day after injection, untoward reaction all disappears.Needleless is noted
Penetrate compared with hand-foot-mouth disease vaccine system has pin intramuscular injection through subcutaneous, intramuscular injection with tradition, the skin injury persistent period
The longest, to injection, untoward reaction in the 5th day all disappears.It is indicated above that Needleless injection vaccine for hand-foot-mouth disease system without
Opinion is respectively provided with good safety through Intradermal, subcutaneous, intramuscular injection.
B, 1, immunity
39 body weight the female small-sized bar horse pig (purchased from Beijing Experimental Animal Center) of 20-25kg be randomly divided into group 1,
Group 2, group 3, group 4, often group 9；PBS group 3；Group 1, group 2, group 3, group 4 are further divided into a, b, c
Three groups, often 3 small-sized bar horse pigs of group；The dosage that a, b, c are tri-groups is respectively the brothers of above-mentioned two preparations of 1.0EU
The vaccine for hand-foot-mouth disease of above-mentioned two preparations of stomatosis vaccine, 2.0EU, the vaccine for hand-foot-mouth disease of above-mentioned two preparations of 3.0EU；
Group 1: use the above-mentioned needle-free injection ampoule being filled with 1.0EU, 2.0EU, 3.0EU vaccine for hand-foot-mouth disease respectively
With needleless injector (Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1), carry out
Immunity, carried out intradermal immunization at the 0th, 28 days, and immunization ways is with the volume of every dose of 0.1ml (can multi-point injection)
It is applied in thigh exterior lateral area, named needleless Intradermal 1.0EU, needleless Intradermal 2.0EU, needleless Intradermal 3.0EU.
Group 2: use the above-mentioned needle-free injection ampoule being filled with 1.0EU, 2.0EU, 3.0EU vaccine for hand-foot-mouth disease respectively
With needleless injector (Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1), carry out
Immunity, carried out subcutaneous inoculation at the 0th, 28 days, and immunization ways is with the volume of every dose of 0.1ml (can multi-point injection)
It is applied in thigh exterior lateral area, named needlefree 1.0EU, needlefree 2.0EU, needlefree 3.0EU.
Group 3: use the above-mentioned needle-free injection ampoule being filled with 1.0EU, 2.0EU, 3.0EU vaccine for hand-foot-mouth disease respectively
With needleless injector (Jiangsu Chengyu MIT Medical Technology Co., Ltd., product type: MP-0.1, MG-0.1), carry out
Immunity, carried out intramuscular immunisation at the 0th, 28 days, and immunization ways is to be applied to big leg outer side with the volume of every dose of 0.5ml
In region, named needleless muscle 1.0EU, needleless muscle 2.0EU, needleless muscle 3.0EU.
Group 4: the needle injection that has using tradition 0.5mm*20mm to be specification carries out immunity, enters respectively at the 0th, 28 days
The vaccine for hand-foot-mouth disease of above-mentioned two preparations of row intramuscular immunisation 1.0EU, 2.0EU, 3.0EU, immunization ways is with every dose of 0.5ml
Volume be applied in thigh exterior lateral area, named have pin 1.0EU, have pin 2.0EU, have pin 3.0EU.
PBS group: the needle injection that has using tradition 0.5mm*20mm to be specification is injected, at the 0th, 28 days respectively
Carrying out intramuscular injection PBS, immunization ways is to be applied in thigh exterior lateral area with the volume of every dose of 0.5ml, named
PBS control group.
2, NAT measures
Within 14 days after each treated animal Full-access immunization, collect serum, use microneutralization test method to measure in the EV71 of serum
And antibody titer.Concrete grammar measures with serum antibody titer after immunity Rhesus Macacus in above-mentioned A immunity.
Result such as table 2, for the level of different group small-sized bar horse pig Post-immunisation serum neutralizing antibodies, it can be seen that small-sized
Bar horse pig through 2.0EU, 3.0EU Needleless injection vaccine for hand-foot-mouth disease systemic vaccination of intradermal injection NAT with
Tradition has the antibody titer of pin intramuscular injection 3.0EU to maintain an equal level；Equally, through bar horse pig through subcutaneous, intramuscular injection 3.0EU
The NAT of Needleless injection vaccine for hand-foot-mouth disease systemic vaccination also has the antibody of pin intramuscular injection 3.0EU with tradition
Titer maintains an equal level.This result show low dose Needleless injection vaccine for hand-foot-mouth disease system at bar horse pig model through intradermal immunization
The neutralizing antibody level having pin injection identical with standard dose muscle can be produced.Meanwhile, this Needleless injection hand-foot-mouth disease epidemic disease
Seedling system also can be through subcutaneous, intramuscular injection, and excitating organism produces identical or higher NAT.
NAT after table 2 small-sized bar horse pig immunity
3, systemic immunity safety evaluatio DRAIZE scoring
In after application Needleless injection vaccine for hand-foot-mouth disease systemic immunity small-sized bar horse pig 5 days, every day observes injection part
The skin injury situation of position, Yin Bama pig is similar to the skin texture of people, therefore applies this model as injection safety
Evaluation more directive significance.And mark according to degree of impairment and degree.Standards of grading are as shown in Figure 3.0 point:
There is no erythema, have no edema；1 point: slight erythema, skin has slight protuberance, is almost difficult to discover；2 points: clear
Erythema, it can be seen that significantly swell；3 points: moderate erythema, the visible limbus of protuberance；4 points: severe erythema, and
There are incrustation and deep lesions.In Fig. 5 represents immunity latter 5 days, each injection system damage to bar horse pig injection site skin
Traumatic condition condition appraisal result, needlefree, intramuscular injection and have pin intramuscular injection DRAIZE appraisal result similar, all at note
Within after penetrating the 1st day and the 2nd day, accidental excoriation and slight erythema occur, inject latter 3 days symptoms and gradually alleviate,
In injection after the 4th day, untoward reaction all disappears.Needleless injection vaccine for hand-foot-mouth disease system has with tradition through intradermal injection
Pin intramuscular injection is compared, and skin injury is relatively light, and skin adverse reaction disappears faster.It is indicated above that Needleless injection hands
No matter foot stomatosis vaccine system is respectively provided with good safety through Intradermal, subcutaneous, intramuscular injection.
Claims (10)
1. Needleless injection vaccine for hand-foot-mouth disease system, for following 1) or 2):
1) system shown in includes the container being filled with vaccine for hand-foot-mouth disease, the fill dosage of described vaccine for hand-foot-mouth disease
Standard dose less than or equal to this vaccine for hand-foot-mouth disease；
2) system shown in includes the container of fill vaccine for hand-foot-mouth disease and readable carrier；In described readable carrier is recorded
Appearance includes: the Needleless injection dosage of described vaccine for hand-foot-mouth disease is less than or equal to this vaccine for hand-foot-mouth disease standard dose.
System the most according to claim 1, it is characterised in that: the fill dosage of described vaccine for hand-foot-mouth disease or
Needleless injection dosage is 1/3-1 times of described vaccine for hand-foot-mouth disease standard dose；
And/or, the fill dosage of described vaccine for hand-foot-mouth disease or Needleless injection dosage all specially 1/3-2/3 times is described
Vaccine for hand-foot-mouth disease standard dose.
System the most according to claim 1 and 2, it is characterised in that:
The fill dosage of described vaccine for hand-foot-mouth disease or Needleless injection dosage are not more than 3.0EU, and are not 0；
And/or, fill dosage or the Needleless injection dosage of described vaccine for hand-foot-mouth disease are specially 1.0EU-3.0EU；
And/or, fill dosage or the Needleless injection dosage of described vaccine for hand-foot-mouth disease are specially 1IU or 2.0EU.
4. according to described system arbitrary in claim 1-3, it is characterised in that: described vaccine for hand-foot-mouth disease is for going out
In live vaccine, attenuated live vaccine, restructuring VLP vaccine, recombinant vaccine, synthetic peptide, DNA vaccination any one
Plant or several mixing.
5. according to described system arbitrary in claim 1-4, it is characterised in that:
1) system shown in or 2) shown in system the most also include supporting with the described container being filled with vaccine for hand-foot-mouth disease
The Needleless injection device used；
And/or, described Needleless injection device is specially needleless injector.
6. according to the system described in claim 1-5, it is characterised in that:
The described container being filled with vaccine for hand-foot-mouth disease is the disposable needle-free injection ampoule being filled with vaccine, comprising:
One body of pre-fill vaccine,
It is integrally formed at a needleless injector joint of described body one end,
In being slidably arranged in described body by the described body other end and close a power push-rod of described body,
It is arranged on the jet in described needleless injector joint,
It is connected to an arresting lever of the front end of described power push-rod easily brokenly,
It is removably disposed on described needleless injector joint and closes a sealing cap of described jet, and
Be removably disposed on described power push-rod and with a sealing lock dog of the entrance tabling of described body；
Wherein, described jet has a locking groove, and described jet is by described locking groove and described tube cavity phase
Connection；Described arresting lever matches with described locking groove.
System the most according to claim 6, it is characterised in that:
The diameter of described power push-rod is consistent with the internal diameter of described body；Described arresting lever and locking groove are taper；Described
Sealing cap uses embedded structure to be removably disposed on described needleless injector joint；
Being provided with sealing lock dog groove on described power push-rod, described sealing lock dog is entrenched in described sealing lock dog groove,
Thus be removably mounted on described power push-rod；
Described sealing cap uses embedded structure to be removably disposed on described needleless injector joint；Described power push-rod
On be provided with sealing lock dog groove, described sealing lock dog is entrenched in described sealing lock dog groove, thus removably pacifies
It is contained on described power push-rod；
Described body, needleless injector joint, jet and locking groove is integrally manufactured forms.
8. according to described system arbitrary in claim 1-7, it is characterised in that:
The fill volume of described vaccine for hand-foot-mouth disease is 0.05-1ml.
9. according to described system arbitrary in claim 1-8, it is characterised in that:
Described readable carrier contents also includes the Needleless injection position of described vaccine for hand-foot-mouth disease and described hand-foot-mouth disease
The Needleless injection mode of disease vaccine；
Described Needleless injection position is Intradermal, subcutaneously or intramuscularly；
Described Needleless injection mode is repeatedly continuous immunity or single immunization.
10. arbitrary described system application in preparation immune animal or people's product in claim 1-9；
Described animal is specially domestic animal, and described domestic animal is especially specially pig or monkey；
Or, a kind of to animal or the method for people's immunity vaccine for hand-foot-mouth disease, for described system arbitrary in claim 1-9
System carries out immunity, and the dosage of described immunity is the Needleless injection dosage in claim 1-9 in arbitrary described system；Institute
The mode stating immunity is specially repeatedly continuous immunity or single immunization；The position of described immunity be specially Intradermal, subcutaneous or
Muscle.
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| CN101448521A (en) * | 2006-03-03 | 2009-06-03 | 梅瑞尔有限公司 | Mycoplasma hyopneumoniae vaccine |
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