CN105999257A - Influenza vaccine needle-free injection system and application - Google Patents
Influenza vaccine needle-free injection system and application Download PDFInfo
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- CN105999257A CN105999257A CN201610308465.2A CN201610308465A CN105999257A CN 105999257 A CN105999257 A CN 105999257A CN 201610308465 A CN201610308465 A CN 201610308465A CN 105999257 A CN105999257 A CN 105999257A
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- A—HUMAN NECESSITIES
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- 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
- 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
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- A61M5/178—Syringes
- A61M5/30—Syringes for injection by jet action, without needle, e.g. for use with replaceable ampoules or carpules
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- 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
- A61M5/31—Details
- A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
- A61M5/31501—Means for blocking or restricting the movement of the rod or piston
- A61M5/31505—Integral with the syringe barrel, i.e. connected to the barrel so as to make up a single complete piece or unit
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- 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
- A61M5/31—Details
- A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
- A61M5/31511—Piston or piston-rod constructions, e.g. connection of piston with piston-rod
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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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- 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
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/30—Vaccines
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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- Animal Behavior & Ethology (AREA)
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
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- Virology (AREA)
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Abstract
The invention discloses an influenza vaccine needle-free injection system and application. The influenza vaccine needle-free injection system comprises a needle-free injection ampoule filled with a vaccine which is monovalent or multivalent, and the HA content of each vaccine in monovalent or multivalent vaccines is 3-15 microgramme. Experiments prove that when the influenza vaccine needle-free injection system is used for immunization, the antigen dosage only accounts for part of a traditional intramuscular injection antigen dosage, and the same or higher HI titer can be generated. It is further indicated that a needle-free immune means is an ideal means capable of being selected by the influenza immunization vaccine.
Description
Technical field
The present invention relates to field of medicaments, especially infectious disease field.More particularly, to Needleless injection influenza epidemic disease
Seedling system and application.It is applicable to all kinds of influenza vaccines Vaccination and Immunoprophylaxis.
Background technology
Optimal vaccine delivery system should have safety, effectiveness and economic and practical, feasible when application
Property convenient, dosage control is convenient, and compliance is good.And vaccine delivery system can effectively prevent illegal and reuse,
Reduce the risk that medical personnel infect.And the most commonly used injection system is, rustless steel is used to make
Entry needle thrusts inoculator thus carries out vaccine or drug injection, and this injection system exists many defects, as crowd is difficult
With the probably pin sense overcome, the unexpected needle sting caused of medical treatment, and the danger etc. brought.In worldwide, often
100 injections just there are 5 needle sting accidents occur.On the contrary, the equipment that the application of needleless immunological technique is special is logical
Cross high-speed jet by vaccine injection in specific tissue depth, it is to avoid the drawbacks described above such as syringe needle exposure, skin damage infection
The harm brought.And needleless immunological technique has, and needleless is painless, easy quickly, economical and efficient and convenient to operate etc. all
Many advantages, the growth field new by becoming immunity inoculation.
Since 1978 introduce trivalent flu, vaccination has become prevention and has controlled the main policies of influenza.Season
Joint property influenza vaccines are usually trivalent vaccine.2011, the seasonal trivalent flu produced in global range was more than 600,000,000
Agent.Trivalent flu vaccine comprises three kinds of influenza virus, includes that two kinds of influenza A and a kind of Type B influenza are sick respectively
Poison.Annual World Health Organization (WHO) can be according to the prediction of the epidemic strain to influenza virus on the horizon, it is recommended that trivalent flu
The composition of vaccine.And trivalent flu is because the protection to influenza B is comprehensive not, in order to increase two kinds of B virus
The protection of strain vaccine, can be effectively by allocating a such vaccine of influenza B virus strain in the pedigree of trivalent flu into
The generation of flu-prevention disease.World Health Organization (WHO) proposes to comprise two about tetravalence influenza vaccines at the beginning of 2012 first
Plant the suggestion of B-mode lineage strain, and this suggestion has been listed in Northern Hemisphere Immunization programme then.Tetravalence influenza virus
Split vaccine comprises tetra-kinds of Virus type influenza stock solutions of H1N1, H3N2, B1, B2, and two kinds of Type B stock solutions exist intersection
Reaction.
The immunogenicity that many researchs it turned out skin is better than muscle or other approach, and skin corium comprises abundant immunity
Cell, intradermal immunization Low dose vaccine is likely to cause the immunoreation being same as full dose muscle vaccine, and this not only saves epidemic disease
Seedling consumption, reduces cost, solves the restriction of vaccine shortage, and meanwhile, it is deep that minimizing vaccine injection amount can also reduce generation
The probability of layer infiltration；Therefore, this technology reduces amount of antigen needed for vaccine, reduces the expense of publilc health economically,
There is abundant predominant face to flu outbreak, and provide possible for large-scale inoculation.
Summary of the invention
It is an object of the present invention to provide Needleless injection vaccine system.
The Needleless injection vaccine system that the present invention provides, for following 1) or 2):
1) system shown in includes the container being filled with vaccine, and the fill dosage of described vaccine is less than or equal to the mark of this vaccine
Quasi-dosage；Wherein, the container being filled with vaccine is the disposable container equipped with vaccine；
2) system shown in includes the container of fill vaccine and readable carrier；Described readable carrier contents includes: institute
State the Needleless injection dosage of vaccine less than or equal to this vaccine standards dosage；Wherein, the container being filled with vaccine is can be repeatedly
The container equipped with vaccine used continuously.
In said system, described in be filled with the needle-free injection ampoule of vaccine and include:
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 fill dosage of described vaccine or Needleless injection dosage are 1/5-1 times of this vaccine standards dosage.
In said system, described vaccine is univalent vaccine or polyvalent vaccine；
In described univalent vaccine or described polyvalent vaccine, fill dosage or the Needleless injection dosage of each vaccine are
1/5-1 times of this vaccine standards dosage.
In said system, described vaccine is viral inactivation vaccine, virolysis vaccine, virus component vaccine, inactivation disease
Poison body, restructuring VLP vaccine, restructuring nano-particle vaccine, attenuated live vaccine, subunit vaccine, DNA vaccination, weight
Group any one of live vector vaccine, universal broad-spectrum vaccine etc. or several mixing, but it is not limited to this.
The dosage form of described 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 vaccine is monovalent influenza vaccine or multivalence influenza vaccines, the needleless note of described influenza vaccines
Penetrate dosage or fill dosage to remember with the HA content of these influenza vaccines；
The fill dosage of each influenza vaccine or Needleless injection agent in described monovalent influenza vaccine or multivalence influenza vaccines
Amount is no more than standard dose 15 μ g, and is not equal to 0；
And/or, the fill dosage of each influenza vaccine or needleless in described monovalent influenza vaccine or multivalence influenza vaccines
Injection dosage is 3-15 μ g；
And/or, the fill dosage of each influenza vaccine or needleless in described monovalent influenza vaccine or multivalence influenza vaccines
Injection dosage is all specially 3-7.5 μ g；
And/or, the fill dosage of each influenza vaccine or needleless in described monovalent influenza vaccine or multivalence influenza vaccines
Injection dosage is all specially 3 or 7.5 μ g.
Influenza vaccines dosage can be standardized by the level with reference to HA in recent years, and HA level is generally by unidirectional spoke
Penetrate shape immunodiffusion SRID test to come quantitatively.Influenza vaccines for intramuscular injection generally comprise the pact from each strain
15μg HA.But, Needleless injection influenza vaccines system uses, by intradermal injection approach, it is not necessary to as intramuscular
Amount of antigen during injection, therefore, in present system, various inactivating influenza virus split vaccines in multivalence influenza vaccines
In HA be from each strain 3-15 μ g；HA is generally every strain less than 15 μ g, preferably 3 μ g, 7.5 μ g
Or 9 μ g.
Vaccine standards dosage is the dosage announced on 2015 editions Chinese Pharmacopoeias, and wherein influenza vaccines standard dose is influenza
Vaccine intramuscular injection dosage, in an embodiment of the present invention, influenza vaccines intramuscular injection dosage is each strain HA15 μ
g。
Influenza vaccines can be various forms of influenza virus vaccine, generally includes live virus or inactivation of viruses.Inactivation stream
Influenza Virus can be whole virus particles, lytic virus granule or subunit vaccine.Can be recombinant influenza strain,
And/or the virus obtained by reverse Genetics Technique.Influenza virus can be attenuation.Can be temperature sensitive,
It can also be Cold tolerance.Can also be to comprise HA and/or the NA viral aliquots in pathogenic strain source and non-pathogenic strain
The reclassification influenza virus in source.Hemagglutinin (HA) is the main immunogens in inactivated influenza vaccine, seasonal current
Influenza vaccine is usually trivalent vaccine or to Type B protection more comprehensively tetravalence influenza vaccines, generally includes two kinds of A type streams
Susceptible strain, and one or both influenza B virus strains.
Described influenza vaccines are specially tetravalence influenza vaccines；Described tetravalence influenza vaccines are split by inactivateing H1N1 influenza virus
Solve vaccine, inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus cracking vaccine 1 and inactivation Type B influenza
Virolysis vaccine 2 forms；Described inactivation H1N1 influenza virus cracking vaccine, inactivation H3N2 influenza virus cracking epidemic disease
The content of the HA of Seedling, inactivation Type B influenza virus cracking vaccine 1 and inactivation Type B influenza virus cracking vaccine 2 is 3
μ g or 7.5 μ g；
Type B in described inactivation Type B influenza virus cracking vaccine 1 and described inactivation Type B influenza virus cracking vaccine 2
Influenza virus is different virus strain.
Described tetravalence influenza vaccines are specifically by inactivation H1N1 influenza virus cracking vaccine (A/California/7/2009
(H1N1) pdm09-like virus), inactivation H3N2 influenza virus cracking vaccine (A/Texas/50/2012
(H3N2)-like virus), inactivation Type B influenza virus cracking vaccine (B/Massachusetts/2/2012-like
Virus) form with inactivation Type B influenza virus cracking vaccine (B/Brisbane/60/2008-like virus)；
In said system, the fill volume of described vaccine is 0.02-1.0ml；Or the fill volume of described vaccine is specially
0.1ml。
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, 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.
Described body, needleless injector joint, jet and locking groove is integrally manufactured forms.
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, 1) system or 2 shown in) shown in system the most also include and the described container being filled with vaccine
Matching used Needleless injection device；
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.
Described readable carrier contents also includes the Needleless injection position of described vaccine, the Needleless injection side of described vaccine
The Needleless injection of formula and described vaccine uses volume；
Described Needleless injection position is Intradermal, subcutaneously or intramuscularly；Described Needleless injection position is specially Intradermal, and not only
It is limited to Intradermal.
Described Needleless injection mode is continuous immunity or single immunization；
It is 0.02-1.0ml that the Needleless injection of described vaccine is intended for single use volume；Or the Needleless injection single of described vaccine makes
It is 0.1ml with volume.
Influenza vaccines volume for intramuscular injection is generally 0.5ml.But, Needleless injection influenza vaccines system is passed through
Intradermal injection approach, it is not necessary to as volume during intramuscular injection, therefore the volume of the present composition is generally less than
0.5ml, preferably 0.1ml.
The application in preparation immune animal or people's product of the above-mentioned Needleless injection influenza vaccines system is also that the present invention protects
Scope；
Described animal is specially domestic animal, and described domestic animal is especially specially pig.
The present invention also protects a kind of to animal or the method for people's flu immunization vaccine, for carrying out immunity by said system, exempts from
Epidemic disease dosage 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 as primary immune-
The elementary cell of the scheme of booster immunization delivers and (this means to carry out antigenicity in several weeks or several months after first time immunity
Similar second time is immune or repeatedly immune).
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.
With conventional have pin intramuscular injection compared with, Needleless injection influenza vaccines system carries out skin immunization and also has a lot of advantage,
If any stronger immunogenicity, it is more easy to enter, pain can be avoided, and reduce inoculation crowd to there being pin injection to fear
Fear, eliminate or reduce the risk of accidental needle sticks wound, be alternatively arranged as a part for cell and immunity system, it is not necessary to
Professional operation, patient can injection etc. voluntarily, therefore can also expand vaccination scope.This kind of method is equally applicable
In the immunity inoculation of rapid, high volume, tackle being very popular or applying in war of infectious disease.
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 present invention provides Needleless injection influenza vaccines system, has pin immunity to note without tradition
Penetrate approach, it is possible to accurately, quickly, painlessly by vaccine inject target area by needleless injector, the most not
The approach needing heavy dose of antigen uses vaccine, and the needle-free injection ampoule of this system pre-fill vaccine can prevent secondary from utilizing,
Avoid the generation of cross-contamination, the pre-fill of vaccine before immunity, improves injection speed, accurate immunizing dose be extensive
Tachysynthesis inoculation provides may.
The immunization ways of the Needleless injection influenza vaccines system of the present invention is a kind of novel immunization strategy, by percutaneous
Immunization route, only needs tradition to have 1/5,1/2 or lower dosage of pin intramuscular injection dosage, gets final product the generation of induction of antibodies
Immune effect with general immunity response；Simultaneously, it is to avoid the immunization ways of syringe needle also has the advantage that 1) use peace
Entirely, easy, quick, and be applicable to mass immunization；2) avoid the probably pin sense of pin injection, reduce
Injection pain, improves the compliance of injection；3) syringe needle is avoided to abuse the cross-contamination brought；4) reduce antigen to use
Amount, reduces production cost.
Present invention demonstrates needle-free injection ampoule and needleless injector use in conjunction when carrying out immunity, the accuracy of injection with
Safety.Combination product is improving Immune efficiency, while saving immunization time, carries for extensive tachysynthesis inoculation
Having supplied may.
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 HI titer with it.Further
Illustrate that Needleless injection influenza vaccines system is the alternative ideal strategy of flu immunization vaccine.
Accompanying drawing explanation
Fig. 1 is 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 the level of the anti-hemagglutinin antibody of H1N1 in 14 days serum after booster immunization.
Fig. 5 is the level of the anti-hemagglutinin antibody of H3N2 in 14 days serum after booster immunization.
Fig. 6 is Type B (B/Massachusetts/2/2012-like virus) in 14 days serum after booster immunization
The level of anti-hemagglutinin antibody.
Fig. 7 is the anti-blood of Type B (B/Brisbane/60/2008-like virus) in 14 days serum after booster immunization
The level of cell agglutinin antibody.
Fig. 8 is that Needleless injection influenza vaccines system is marked through the DRAIZE of intradermal injection pig.
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.
In each embodiment, the μ g of influenza vaccines refers to the content of HA.
Embodiment 2, the preparation and application of Needleless injection influenza vaccines system
The Needleless injection influenza vaccines system of the present embodiment include fill be not more than influenza vaccines standard dose 15 μ g (with
HA content remember) needle-free injection ampoule and matching used needleless injector.
One, the injection depth of Needleless injection influenza vaccines 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 Needleless injection influenza vaccines system that the present invention uses
Liquid can be injected in epidermis by system exactly, and no liquid is injected in muscle sites.
Two, the preparation of Needleless injection influenza vaccines system
Needleless injection influenza vaccines system include being filled with the tetravalence influenza vaccines of various dose needle-free injection ampoule and
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 tetravalence influenza vaccines of various dose for being filled with 3 μ g-7.5 μ g influenza vaccines
The container of standard.
It is 3 μ g-7.5 μ g that description records the Needleless injection dosage of influenza vaccines, and Needleless injection position is the most subcutaneous,
Needleless injection mode is single immunization or continuous immunity.
1, the acquisition of tetravalence influenza vaccines
The each strain of tetravalence influenza vaccines is the 2014-2015 year Northern Hemisphere Seasonal Influenza Vaccine strain that WHO recommends, H1N1
Influenza virus cracking thing (A/California/7/2009 (H1N1) pdm09-like virus), H3N2 influenza virus
Lysate (A/Texas/50/2012 (H3N2)-like virus), Type B influenza virus cracking thing
(B/Massachusetts/2/2012-like virus) and Type B influenza virus cracking thing
(B/Brisbane/60/2008-like virus) forms；Wherein, H1N1 influenza virus cracking thing, H3N2 influenza
HA content in virolysis thing, Type B influenza virus cracking thing and Type B influenza virus cracking thing is than usually 1:1:
1:1.
Above-mentioned H1N1 influenza virus (A/California/7/2009 (H1N1) pdm09-like virus), H3N2 stream
Influenza Virus (A/Texas/50/2012 (H3N2)-like virus), Type B influenza virus
(B/Massachusetts/2/2012-like virus) and Type B influenza virus (B/Brisbane/60/2008-like
Virus) all record in the following literature: Recommended composition of influenza virus vaccines for use in
the 2014-2015northern hemisphere influenza season:
http://www.who.int/influenza/vaccines/virus/recommendations/201402_recommendation.pdf？Ua=1.
Above-mentioned each lysate is prepared as follows:
H1N1 influenza virus (A/California/7/2009 (H1N1) pdm09-like virus) and H3N2 influenza
Virus (A/Texas/50/2012 (H3N2)-like virus) inoculation 9-11 day instar chicken embryo, in 33 DEG C-35 DEG C trainings
Support 48 hours, Type B influenza virus (B/Massachusetts/2/2012-like virus) and Type B influenza virus
(B/Brisbane/60/2008-like virus) inoculates 9-11 day instar chicken embryo, cultivates 72 hours in 33 DEG C-35 DEG C,
The urine of results.Application low speed centrifuge 4000rpm/min is centrifuged 20min and removes macromolecular substances, clarifies restrovirus
Allantoic fluid concentrates 30-50 times with 100-300KD membrane type ultrafilter respectively, uses sucrose density gradient method, warp
30000rpm/min, centrifugal 3 hours, removes in viral concentration liquid the impurity such as major part ovalbumin, formalin-inactivated,
Obtain inactivateing H1N1 influenza virus, inactivation H3N2 influenza virus, inactivation Type B influenza virus
(B/Massachusetts/2/2012-like virus) and inactivation Type B influenza virus
(B/Brisbane/60/2008-like virus) with CTAB cracking crack respectively above-mentioned inactivation H1N1 influenza virus,
Inactivation H3N2 influenza virus, inactivation Type B influenza virus (B/Massachusetts/2/2012-like virus) and
Inactivation Type B influenza virus (B/Brisbane/60/2008-like virus), then by sucrose density gradient method
30000rpm/min is centrifuged 3 hours, applies 10KD ultrafilter membrane filter wash impurity, obtains inactivateing H1N1 influenza virus cracking
Vaccine, inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus (B/Massachusetts/2/2012-like
Virus) split vaccine and inactivation Type B influenza virus (B/Brisbane/60/2008-like virus) split vaccine；
Will inactivation H1N1 influenza virus cracking vaccine, inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza disease
Poison (B/Massachusetts/2/2012-like virus) split vaccine and inactivation Type B influenza virus
(B/Brisbane/60/2008-like virus) split vaccine mixes according to HA content 1:1:1:1, obtains four
Valency influenza vaccines.
2, the needle-free injection ampoule of the tetravalence influenza vaccines of various dose it is filled with
The needle-free injection ampoule of the tetravalence influenza vaccines being filled with various dose is following three kinds:
Being filled with the needle-free injection ampoule of 3 μ g tetravalence influenza vaccines, wherein 3 μ g tetravalence influenza vaccines are by inactivateing H1N1
Influenza virus cracking vaccine, inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus
(B/Massachusetts/2/2012-like virus) split vaccine and inactivation Type B influenza virus
(B/Brisbane/60/2008-like virus) split vaccine forms, inactivation H1N1 influenza virus cracking vaccine,
Inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus (B/Massachusetts/2/2012-like
Virus) split vaccine and inactivation Type B influenza virus (B/Brisbane/60/2008-like virus) split vaccine
The content of HA be 3 μ g respectively；Tetravalence influenza vaccines fill cumulative volume is 0.1ml；
Being filled with the needle-free injection ampoule of 7.5 μ g tetravalence influenza vaccines, wherein 7.5 μ g tetravalence influenza vaccines are by inactivateing
H1N1 influenza virus cracking vaccine, inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus
(B/Massachusetts/2/2012-like virus) split vaccine and inactivation Type B influenza virus
(B/Brisbane/60/2008-like virus) split vaccine forms, inactivation H1N1 influenza virus cracking vaccine,
Inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus (B/Massachusetts/2/2012-like
Virus) split vaccine and inactivation Type B influenza virus (B/Brisbane/60/2008-like virus) split vaccine
The content of HA be 7.5 μ g respectively；Tetravalence influenza vaccines fill cumulative volume is 0.1ml；
Being filled with the needle-free injection ampoule of 15 μ g tetravalence influenza vaccines, wherein 15 μ g tetravalence influenza vaccines are by inactivateing
H1N1 influenza virus cracking vaccine, inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus
(B/Massachusetts/2/2012-like virus) split vaccine and inactivation Type B influenza virus
(B/Brisbane/60/2008-like virus) split vaccine forms, inactivation H1N1 influenza virus cracking vaccine,
Inactivation H3N2 influenza virus cracking vaccine, inactivation Type B influenza virus (B/Massachusetts/2/2012-like
Virus) split vaccine and inactivation Type B influenza virus (B/Brisbane/60/2008-like virus) split vaccine
The content of HA be 15 μ g respectively；Trivalent flu vaccine fill cumulative volume is 0.1ml；
Respectively above-mentioned 3 kinds are filled with during use needle-free injection ampoule and the needleless injector (Jiangsu of tetravalence influenza vaccines
Cheng Yu meter Te medical science and technology company limited, product type: MP-0.1, MG-0.1)；Connect.
Three, Needleless injection influenza vaccines systematic difference
1, immunity
18 body weight are randomly divided into group the female small-sized bar horse pig (purchased from Chinese Academy of Sciences's Experimental Animal Center) of 20-25kg
1 and group 2, often group 9；Group 1 and group 2 are further divided into a, tri-groups of b, c, often 3 miniature pigs of group；
The dosage that a, b, c are tri-groups be respectively above-mentioned two preparations of 3 μ g tetravalence influenza vaccines (remembering with the amount of influenza virus HA),
The tetravalence influenza vaccines (remembering with the amount of influenza virus HA) of above-mentioned two preparations of 7.5 μ g, the four of above-mentioned two preparations of 15 μ g
Valency influenza vaccines (are remembered with the amount of influenza virus HA)；
Group 1: use and above-mentioned be filled with 3 μ g, 7.5 μ g, the needle-free injection ampoule of 15 μ g tetravalence influenza vaccines 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 day and the 14th day, and immunization ways is to be applied to thigh with the volume of every dose of 0.1ml
In inside region, named needleless 3 μ g, needleless 7.5 μ g, needleless 15 μ g.
Group 2: the needle injection that has using tradition 0.5mm*20mm to be specification carries out immunity, at the 0th day and the 14th day
Carry out the tetravalence influenza vaccines of above-mentioned two preparations of intramuscular immunisation 3 μ g, 7.5 μ g, 15 μ g respectively, immunization ways be with
The volume of every dose of 0.1ml is applied in inside thigh areas, named has pin 3 μ g, has pin 7.5 μ g, has pin 15
μg。
2, serum HI titration
Within 14 days after each group of booster immunization, gather blood sample, analyze the anti-blood of relevant strains in serum by hemagglutination inhibition reaction
Cell agglutinin antibody.Test serum and RDE (vibrio cholera filtrate is ground purchased from Japan is raw, article No.: 340016) are with 1:
After 3 mixings, hatch 16-18 hour for 37 DEG C, hatch 30 minutes for latter 56 DEG C.Imitate according to corresponding Influenza virus strain blood clotting
Valency 4 HAUs of configuration, by test serum and the Influenza virus strain effect 1 hour of different extension rates, add
1% chicken red blood cell, room temperature stands 30 minutes.When in negative hole, erythrocyte natural downslide presents teardrop shaped, to have occurred
The inverse of the serum highest dilution of full suppression is NAT.
Fig. 4, Fig. 5, Fig. 6 and Fig. 7 represent after booster immunization H1N1, H3N2, two kind of Type B in 14 days serum respectively
The level of anti-hemagglutinin antibody, wherein B1 is inactivation Type B influenza virus
(B/Massachusetts/2/2012-like virus) split vaccine, B2 is inactivation Type B influenza virus
(B/Brisbane/60/2008-like virus) split vaccine；It can be seen that 3 μ g and 7.5 μ g Needleless injections
The antibody titer of influenza vaccines systemic vaccination has the needle injection antibody titer through intramuscular injection apparently higher than through tradition.
3, Needleless injection influenza vaccines systemic immunity safety evaluatio DRAIZE scoring
In after application Needleless injection influenza vaccines systemic immunity miniature pig 7 days, observe the skin of injection site every day
Degree of impairment.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, can see
To significantly protuberance；3 points: moderate erythema, the visible limbus of protuberance；4 points: severe erythema, and have incrustation and deep
Degree damage.Appraisal result is shown in Fig. 8, and needleless intradermal injection is similar to there being pin intramuscular injection DRAIZE appraisal result, all exists
Accidental excoriation and slight erythema occurred in after injection the 1st day and the 2nd day.And the 4th day after injection, bad
Reaction all disappears.It is indicated above that needleless intradermal injection is respectively provided with good safety with there being pin intramuscular injection.
Claims (10)
1. Needleless injection vaccine system, for following 1) or 2):
1) system shown in includes the container being filled with vaccine, and the fill dosage of described vaccine is less than or equal to this vaccine
Standard dose；
2) system shown in includes the container of fill vaccine and readable carrier；Described readable carrier contents includes:
The Needleless injection dosage of described vaccine is less than or equal to this vaccine standards dosage.
System the most according to claim 1, it is characterised in that be filled with the needle-free injection ampoule of vaccine described in:
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.
System the most according to claim 1 and 2, it is characterised in that: the fill dosage of described vaccine or needleless
Injection dosage is 1/5-1 times of this vaccine standards dosage.
System the most according to claim 2, it is characterised in that:
Described vaccine is univalent vaccine or polyvalent vaccine；
In described univalent vaccine or described polyvalent vaccine, fill dosage or the Needleless injection dosage of each vaccine are
1/5-1 times of this vaccine standards dosage.
5. according to described system arbitrary in claim 1-4, it is characterised in that:
Described vaccine is viral inactivation vaccine, virolysis vaccine, virus component vaccine, inactivation of viruses body, restructuring VLP
Vaccine, restructuring nano-particle vaccine, attenuated live vaccine, subunit vaccine, DNA vaccination, recombinant live-vector vaccine,
Any one of universal broad-spectrum vaccine etc. or several mixing.
6. according to described system arbitrary in claim 1-5, it is characterised in that:
Described vaccine is monovalent influenza vaccine or multivalence influenza vaccines, the fill dosage of described influenza vaccines or Needleless injection
Dosage is remembered with the HA content of these influenza vaccines；
The fill dosage of each influenza vaccine or Needleless injection agent in described monovalent influenza vaccine or multivalence influenza vaccines
Amount is no more than 15 μ g, and is not equal to 0；
And/or, the fill dosage of each influenza vaccine or needleless in described monovalent influenza vaccine or multivalence influenza vaccines
Injection dosage is all specially 3-15 μ g；
And/or, the fill dosage of each influenza vaccine or needleless in described monovalent influenza vaccine or multivalence influenza vaccines
Injection dosage is all specially 3-7.5 μ g；
And/or, the fill dosage of each influenza vaccine or needleless in described monovalent influenza vaccine or multivalence influenza vaccines
Injection dosage is all specially 3 or 7.5 μ g.
7. according to described system arbitrary in claim 1-6, 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:
1) system shown in or 2) shown in system the most also include and the described matching used nothing of container being filled with vaccine
Needle injection device；
And/or, described Needleless injection device is specially needleless injector；
And/or, the fill volume of described vaccine is 0.02-1.0ml.
9. according to described system arbitrary in claim 1-8, it is characterised in that:
Described readable carrier contents also includes Needleless injection position and the Needleless injection of described vaccine of described vaccine
Mode；
Described Needleless injection position is Intradermal, subcutaneously or intramuscularly；
Described Needleless injection mode is continuous immunity or single immunization.
10. arbitrary described Needleless injection vaccine system answering in preparation immune animal or people's product in claim 1-9
With；
Described animal is specially domestic animal, and described domestic animal is especially specially pig；
Or, a kind of to animal or the method for people's flu immunization vaccine, for entering by described system arbitrary in claim 1-9
Row immunity, immunizing dose is the Needleless injection dosage in claim 1-9 in arbitrary described system；Immunization ways is concrete
For repeatedly continuous immunity or single immunization；Immunity position is specially Intradermal, subcutaneously or intramuscularly.
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Effective date of registration: 20180403 Address after: 130507 Jilin province Changchun nine Economic Development Zone West Road No. 888 Applicant after: Changchun Haijiya Biotechnology Co., Ltd. Address before: Nine Station Road Economic Development Zone in Jilin province 130507 Changchun No. 888 Applicant before: Changchun Haijiya Biotechnology Co., Ltd. Applicant before: Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, PR China |
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