WO2007117964A2 - Apparatus and method for vaccine development using ultrasound technology - Google Patents

Apparatus and method for vaccine development using ultrasound technology Download PDF

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Publication number
WO2007117964A2
WO2007117964A2 PCT/US2007/064842 US2007064842W WO2007117964A2 WO 2007117964 A2 WO2007117964 A2 WO 2007117964A2 US 2007064842 W US2007064842 W US 2007064842W WO 2007117964 A2 WO2007117964 A2 WO 2007117964A2
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Prior art keywords
solution
ultrasound
tip
energy
ultrasonic
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PCT/US2007/064842
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French (fr)
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WO2007117964A3 (en
Inventor
Eilaz P. Babaev
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Babaev Eilaz P
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Priority to EP07759299A priority Critical patent/EP1998803A4/en
Priority to JP2009503185A priority patent/JP2009531454A/en
Publication of WO2007117964A2 publication Critical patent/WO2007117964A2/en
Publication of WO2007117964A3 publication Critical patent/WO2007117964A3/en

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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
    • C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/06—Hydrolysis; Cell lysis; Extraction of intracellular or cell wall material
    • 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
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/06—Lysis of microorganisms
    • C12N1/066—Lysis of microorganisms by physical methods
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/521—Bacterial cells; Fungal cells; Protozoal cells inactivated (killed)
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5252—Virus inactivated (killed)

Definitions

  • the present invention relates to the development of vaccines
  • the present im ention relates to apparatus and methods for developing vaccines lining ultrasound tec Sinolog ⁇ .
  • Inactivated vaccines flu. cholera, hepatitis A
  • ⁇ accines are considered stable and ielath eh safe since 0 they cannot revert to the virulent (disease-causing) form.
  • the second classical approach to the pioduction ⁇ f v accines is an attenuated or IKe vaccine (measles, mumps, rubella)
  • IKe vaccine measles, mumps, rubella
  • the disease-causing organism is grown under special laboratory conditions that cause it to loose its ⁇ irulence or disease causing properties. Products prepatcd in this way lequire special handling and storage m order to maintain then potency
  • These products produce both anti-body mediated and
  • AHigcr treats substantial K ⁇ iab1e cells, bacteria, or ⁇ iiuses (i e. those that are mtact and capable of functioning) with uih abound in order to make a ⁇ ailable antigens capable of inducing an immunogenic and or therapeutic response Specifically, the treatment of cells and viruses with ultrasound is intended to deactivate the potential!) harmful cells and ⁇ mises and to also disperse the antigens present for use as a ⁇ aceine without fuither processing.
  • ALHgci recommends that the procedure is conducted at ioom tempeurture whiie maintaining the temperature of the sample containing the microbe against which a vaccine is developed between zero and 5 degrees Celsius. The minimization of heat is to pie ⁇ ent the den aiming of the antigens.
  • Aihgei iurther states that the time must be sufficient to disrupt the v ⁇ uses or cells so that no ⁇ irulent cell structme remains, to do this.
  • ⁇ ihger states that one gsam of cultured cells may generally tequire about 3 minutes of sonication
  • the present h ⁇ entio ⁇ is directed towards m ⁇ tovements of apparatuses and methods for the creation of ⁇ acci ⁇ es using ultrasound waves previously researched and tested h ⁇ the author of this patent in the 19S0's.
  • Appaiatus and methods in accordance with the present invention may meet the abo ⁇ e-rae ⁇ tioned needs and also p ⁇ o ⁇ ide additional ad ⁇ antayes and im ⁇ ro ⁇ ements that will be recognized by those skilled in the art upon rc ⁇ iew of the present disciosuie.
  • the present invention comprises an ultrasonic ge ⁇ craioi, an uitrasoiuc iransducei, a sonicatton tip, and a ⁇ ial oi container of a solution that can be sonicated to create ⁇ accines.
  • fhe solution contained in the vials is a mass of ⁇ iruses, bacteria, oi othci infectious agents
  • the solution is sonicated with uluasound wa ⁇ es to destrov the ⁇ iable infectious ⁇ irus bacterium or infectious agent while also ieleasing the appropriate antigens, thus iesullmg in a vaccine for that virus, bacterium, or other infecrious agent.
  • Ultrasound waves can be de!i ⁇ ered to the solution eithet directly through the insertion of the ultiasound tip into the solution, through a coupling medium, or through an air gas medium
  • the ultrasound tip that is used can vary depending upon the type of del ⁇ er> method chosen
  • the first method uses tx special shaped ⁇ iai where the ultrasound tip remains in the same position during the delivery of the ultrasound energy while the last two methods utilize movement of the ultrasound tip during the sonication treatment.
  • T are also different types of recommended methods for sonicating the solution through a coupling medium
  • a coupling medium There can be a medium placed between the tip and the ⁇ ml, there can be a liquid medium through which to deliver ultrasound waves, or the ⁇ iai containe* itself can be used as a medium if the tips is pressed up against the v ial/container.
  • the sonication time of the solution can vary.
  • the intensity of the ultrasound waves can be controlled through a ⁇ ariaiion in the ultrasound parameters such as the frequency, the amplitude, and the treatment time
  • the process may require different intensity levels and ultrasound parameters based on the specific type of virus, bacterium or other infectious agent used to create the vaccine and based on the volume of the solution containing microbes to he sonicated
  • T he invention is related to the apparatus and methods of deliv ering ultrasound energy to viruses, bacteria, or other infectious agents in order to create a vaccine to treat the virus, bacteuum, oi infectious agent.
  • One aspect of this im ention may be to pro ⁇ sde a method and dev ice foi the creation of different v accines.
  • Another aspect of the invention may be to pro ⁇ ide a method and dev ice for ihe creation of ⁇ acci ⁇ es without the risk of toxicity that occurs with other chemical and tempeiature cieatioa methods
  • Another aspect of the invention ma ⁇ be to pro ⁇ ide a method and de ⁇ ice for the creation of high quality vaccines
  • Another aspect of the indention may be to pan ide a method and device i ' oi the improvement of ⁇ accine creation methods without using temperature or chemical influences
  • Another aspect of the invention may be to pro ⁇ ide a method and de ⁇ ice for the creation of vaccines vuth a decreased production time
  • ⁇ nothei aspect of the invention mas be to pro ⁇ ide a method and de ⁇ ice for the continuous production of vaccines
  • Another aspect of the invention may be to pro ⁇ ide a method and de ⁇ ice for the mass produc ⁇ on of ⁇ acci ries
  • Figure 1 is a perspective ⁇ lew of an ultrasound ⁇ accme development system where the ultrasound tip is inserted into the solution.
  • Figure 2 is a cross-sectional view of an ultrasound tip connected ⁇ ia a coupling medium to a ⁇ ial
  • Figure 3 is a cross-sectional view of an ultrasound tip inserted into a liquid bath with a vial also inserted into the bath to del ⁇ cr ultrasound energy through the liquid to the vial.
  • Figure 4 is a cross-sect son a 1 ⁇ je ⁇ s of an ultrasound tip inserted into a vial but located at a distance from the solution in the vial.
  • Figure 5 are cross- sectional views of example ultrasound tips for use in the ultrasound ⁇ accine development ⁇ .) ste ⁇ n.
  • Figure 6 are cioss-seetional ⁇ iews of example different shaped ⁇ ials foi use m the ultrasonic vaccine development s ⁇ stem where the tip is inserted directly into the solution and sonicates the solution from a constant position
  • Figure 7 is a cross- sectional ⁇ ie ⁇ of recommended sonication methods to use with the ultrasound vaccine de ⁇ elopment system wheie the tip is insetted into the solution nn ⁇ moxes during sonication
  • Figure 8 is a cross-sectional view of a production- tine method to use with the ultrasound ⁇ accine development system
  • Figure 9 is a cross-sectional ⁇ iew of a eaiousel method to use with the ultrasound vaccine development system.
  • Fig, 1 illustrates the vaccine creation apparatus that has an ultrasonic generator 1. an ultrasonic transducer 2, a sonication tip 3. and a via! 4 or other container in which a solution vviil be placed.
  • the solution in the vial or container is a mass of viruses, bacteria, or other infectious agents.
  • the solution is sonicated with ultrasound waves to destroy the viable infectious vims, bacterium, or other infectious agent while aiso releasing the appropriate antigens, thus resulting in a vaccine against that virus, bacterium, other infectious agent. Because the resulting vaccine is available for immediate use, the production time of vaccines developed through this method is lower than the production time of vaccines developed through classical methods mentioned above.
  • Ultrasound waves can be delivered to solution either directly through the insertion of the ultrasound tip into the solution Fig. 1 , through a coupling medium adjacent to the vial Fig. 2 or near the vial Fig. 3, or through the air or gas medium Fig. 4.
  • Fig. 5 shows examples of recommended ultrasound tips that can be used depending on the type of delivery method.
  • Fig. 5a is a spherical ultrasound tip 13 and
  • Fig. 5b is a spherical ultrasound tip 14 that contains a centra! orifice 15.
  • Figs. 5c/5d/5e/5f show ultrasound tips with a flat radiation surface.
  • Figs. 5c and Se are ultrasound tips 16 and I? with a fiat radiation surface
  • Figs. Sd and 5f are ultrasound tips 17 and 20 with flat radiation surfaces and central orifices 18 and 21.
  • Figs. 5g and 5h show ultrasound tips 22 and 23 with a curved radiation surface - Fig.
  • Se shows an ultrasound tip 23 with a curved radiation surface mid a central orifice 24,
  • the central orifices of the ultrasound tips shown in Fig. 5 can be used to deliver solution into a vial or container and/or can be used to provide sonication during or after delivery of the solution.
  • Fig. J shows direct sonication where the ultrasound tip 3 is inserted into the vial 4 and into the solution - the recommend tip 3 to use is either a sphere Figs, 5a/5b, a flat radiation surface Figs. 5c/5d/5e/5f, a rectangular prism (not shown), or another similar shape or combination of shapes, with the sphere Figs. 5a/5b as the preferred tip.
  • the most preferred tip is the spherical tip 14 that contains a central orifice 15; this is because the most preferred treatment method m ⁇ ol ⁇ es the use of a sphencai sonication tip ⁇ heie the solution is delr ⁇ ered into the ⁇ mi or container through the centra! orifice
  • Fig. 2 shows deb ⁇ ci ⁇ of ultrasound energv fi ⁇ m an uiUasound tip 5 thiough a coupling medium 6 such as liquid gel, ot the glass plastic ⁇ ial 7, v * heie the tip 5 is pressed up against the S ⁇ m ⁇ 7 or container —
  • the lecommendcd configuration of tip 5 is one that matt he* * the shape of tip 5 to the geometric shape of the ⁇ ml 7 or contamei l ⁇ or example, if a sphencai ⁇ ia1 is to be sonicated the recommend tip would be a curved-shape tip (not shown) t»o that the tip would fit atound the shape of the ⁇ ial
  • Fig. 3 show s deb ⁇ er> of ultrasound energv ftor ⁇ an ultiasound tip 8 thiough a liquid !0 medium 9
  • the ultiasound Up 8 JS located at a d ⁇ &tance from the ⁇ ial 10 -the recommended up to use is a Oat shaped tip Fig. 5c/Fig. 5d w nh the prefcucd tip being a flat shaped tip without a central office as depicted m Fig. 5c.
  • the ultiasound tip 8 is. placed into the liquid medium 9 and delrveis ultrasound eneigx to the ual l ⁇ thtough the liquid medium 9
  • FIg. 4 show s delrv er> of ultrasound energv fior ⁇ m ⁇ ultiasound tip 1 1 to a ⁇ ial ⁇ 2 thiough 1 ⁇ an ait or gas medium - the recommended tip to use is a flat-shaped tip Fig. 5c/5d/5e/5f, w Uh the conductedned tip eithe ⁇ Fig. 5c oi 5c Foi ⁇ is delneiy method the ullrasomid tip 1 ⁇ is inserted into the ⁇ ial 12 but the tip 11 does not come into contact ⁇ ith the solution m the ⁇ ml 12,
  • Fig. 1 shows delncix of ultiasound eneig ⁇ where the ultrasound tip 3 is inserted into the viai 4 and into the solution there are three different ts pes of recommended methods for this 0 direct somcatio ⁇
  • Fig. 6 show s the first method that uses a special shaped ⁇ sal wha e the ultrasound tip tema ⁇ is m the same position du ⁇ ug the delnerv of the uliiasound eneigv while Fig. 7 s! ⁇ nvs the last two methods that utilize moxement of the ultrasound tip during the somcation treatment
  • Fig. 6 shows the fust method of duect somcation that uses both a special shaped ⁇ ial 26 5 28, oi 30 and a corresponding ultrasound t ⁇ 25, 27, oi 29 that mmois the shape of the ⁇ iai 26 28, or 30
  • Theie aie thiee dsffeie ⁇ f jet ⁇ mni ⁇ nded shapes oi ⁇ ials 26 28, O ⁇ 30 to use w ith a couc&pondmg ulua&ound tip 25, 27, or 29 the three bhapcs aie Fig, 6a a spherical ⁇ tal 26, Ftg. 6b a tectangulai ⁇ ial 28, and Fig.
  • 6c a cuned ⁇ ia! 30
  • a spherical shaped ultiasound tip 25 is inseited into the bortom of the ⁇ ial 26
  • the ⁇ O ultrasound tip 25 m ⁇ rors the shape of the ual 26
  • This same concept of equal sonication also applies to the rectangular shaped ⁇ ial 28 shown in Fig. 6b.
  • Fig. 6 shows the second potential method of direct sonicaiion where the ultrasound tip 31 is inserted uno the bottom of the via!
  • the ultrasound tip 31 gradually rises to the top of the solution while delivering ultrasound energy
  • the ultrasound tip 31 stops its movement and stops delivering ultrasound energy after it reaches the top and the entire solution has been sonicated This movement during the delivery of ultrasound energv allows for equal sonication of the entire solution, which is effective because it ensures that the harmful cells and viruses are destroyed to prevent toxicity and that the antigens are released.
  • Fig. 7 also shows the third potential method of direct sonication wheie the ultrasound tip 31 is inserted into the bottom of the vial 32 containing solution and the tip 31 rises m a step- mode motion 34 Sonication occurs for a brief time and then stops. The ultrasound tip 31 is moved slightly higher, and then sonication occms again.
  • This step-delhery motion 34 is repeated until the tip 31 has mo ⁇ ed to the top and the entire solution has been sonicated Simiiarh to the continuous movement deli ⁇ er>, this method allows for equal sonication of the entire solution
  • This distance between delne ⁇ steps in this step-mode delivery- method can be of equal or v arying distances
  • Fig, S shows a cross-sectional ⁇ ie ⁇ v of a production- Hoe somcation method to use ⁇ v ith the ulttasound vaccine de ⁇ elopment system Y ials 38 men e down the product ton line towards tiie ultrasound tip 3$.
  • the tip 35 mo ⁇ es down 37 into the ⁇ ial 36 to sonicate the solution contained in the vjal 36, After sonication, the ultrasound tip 35, mo ⁇ es back up 37 and warts until another ⁇ Ia! 38 moves to the ultrasound tip 37. This process is repeated to sonicate multiple ⁇ iais 38.
  • the solution can be inserted m the ⁇ sals 38, Pre-filled vials 38 can be placed on the line, the ultrasound tip 37 can fill the % ial 36 v, ith the solution tluough a central oullce (not shown) m the ultrasound tip 37, or there can be a separate delivery mechanism source or sources (not shc ⁇ ui) that can till the ⁇ sals 38 as they mo ⁇ e down the production line and towards the ultrasound rip 35.
  • one or more ultrasound lips can deliver ultiasonic cnctgy to one ot moi ⁇ ⁇ sals at a time.
  • 9 is a cross-sectional ⁇ iew of a carousel somcation method to use uith the ulltasound vaccine development s> stem.
  • Vials 42 are placed in the carousel system and rotate around the caiousel until they reach the ultrasound tip 39
  • the ⁇ ial 40 readies the ultrasound tip 39
  • the tip 39 mo ⁇ es down 41 into the vial 40 to sonicate the solution contained in the vial 40.
  • the ultrasound dp 39 rames back up 41 and wails until another ⁇ ial 42 moves to the ultrasound dp 39.
  • the son teat ion time of the solution can be from fractions of a second and above for both pulse and continuous waxe mode delnery. Ilowe ⁇ c ⁇ , the intensity of the ultrasound waves can be controlled through a variation in the
  • the recommended frequency iange for the ultrasound wa ⁇ es is ⁇ 6 k! ⁇ / to 20 MI i/. with the pretested frequency range of 30 kHz 120 kH?, and the most preferred frequency ⁇ aiue is 50 kHz
  • the amplitude of the ultrasound waves can be 2 microns and abo ⁇ e. with the recommended amplitude to be in tange of 3 microns to 250 miaous, and the most preferred amplitude value is 8(3 microns.
  • the recommended sonication treatment time is 5 10 seconds.
  • Hie amount of solution in the ⁇ ial is at least 1 grams, and the pieferred amount of solution is 5 IO grains.
  • the process may requiie different intensity levels and ultrasound parameters based on the specific type of ⁇ irus, bacterium, or other infectious agent used to create the vaccine and based on the amount of the solution to be sonicated l j or example, 5 ml of a solution can be sonicated with an ultrasound frequency of 50 kHz.
  • an amplitude of p-p 50 microns, an ⁇ nlens ⁇ t> of about ⁇ flOO watts cm 2 , and the sonication time will take up to 10 seconds based on the type of virus, bacterium, etc solution
  • the sonication of the solution can be conducted tn drffeient temperature ens tronmems. but the preferred method is to use roor ⁇ temperature.

Abstract

Method and device for the creation of vaccines using ultrasonic waves, comprised of an ultrasound generator and a transducer to produce ultrasonic waves, is disclosed. The transducer has a specific ultrasound tip depending upon the type of delivery method utilized and depending on the shape of the vial containing the solution of the virus, bacterium, or other infectious agent. The apparatus delivers ultrasonic waves to solution either directly through the insertion of the ultrasound tip into the solution through a coupling medium adjacent to the vial or near the vial, or through an air or gas medium. The ultrasound waves have the effect of destroying the viable virus, bacterium, or other infectious agent and of releasing the appropriate antigens, thus resulting in a vaccine for that virus, bacterium, or other infectious agent.

Description

APPRATUS AND METHODS FOR VACCINE DEVELOPMENT USING ULTRASOUND TECHNOLOGY
APPARATUS AM) METHODS KOR VAC CINE DEVELOPMENT I'SING
LLTR-VSOl1ND rECHNOLOGY
BACKGROUND OF XI I M INVTN DON ? Field of the Im ention
The present invention relates to the development of vaccines In particular, the present im ention relates to apparatus and methods for developing vaccines lining ultrasound tec Sinolog} .
Description of the Related Art:
I O Vaccine research and dev elopmem has seen an increased level of activity, especially
\\ ith the recent dev elopment of biodefense initiati\ es. The process of recombinant genetic engineering has pro\ ided a potential new approach to creating new and improved \ accines for the treatment of disease. So far, this approach has met with limited success for a vaπelv of reasons, and thus many \ accines are still produced via traditional methodologies. i 5 Most classical \ accines are produced by one of two production methods that create either an inactivated (killed) oi attenuated (lnej saccule product
Inactivated vaccines (flu. cholera, hepatitis A) are produced b> killing the disease causing microorganism A number of different methods of inactiv atiυn can be used, including chemicals, irradiation, or heat These \ accines are considered stable and ielath eh safe since 0 they cannot revert to the virulent (disease-causing) form. The products often do not require refrigeration, a quality that makes them accessible and desirable to domestic healthcare personnel as well as those in developing countries because they are practical for \ accinating people who aie in remote locations or involved in highly mobile actix ities (such as members of the armed force } \ However, most inactiv ated vaccines produce a relatively weak immune 5 response and must be given more than once Λ vaccine that requires multiple doses (boosters) may have a limited usefulness, especially in areas where people have limited access to regular healthcare
The second classical approach to the pioduction υf v accines is an attenuated or IKe vaccine (measles, mumps, rubella) The disease-causing organism is grown under special laboratory conditions that cause it to loose its \ irulence or disease causing properties. Products prepatcd in this way lequire special handling and storage m order to maintain then potency These products produce both anti-body mediated and ceii-mediated immunity, and generaih they wiϊl only require one booster dose. While Su e vaccines do have some higher immune response adxaotagev this method of production has one large drawback Because the organisms ate still Ih ing it is their nature to change 01 imitate, causing these pioducts to ha\c a remote possibility that the organisms may re\crt to a \irulent foπn and potentially cause disease, thus, infection may occur either as a result of exposure while handling processing the vaccine or alter administration of the \accine rheiefme, these \ accines must be carefully tested and monitored Patients who ha\ e compromised immune systems are not usual K administered li\e \accmes
These two classical approaches to vaccine development and production not only make up the majority of \ accin.es in use toda> , but these approaches continue to be used m current vaccine development programs, including the dex elopment of vaccines for HIV Λ1DS, new Iy identified \ ariant strains of f ϊcpatitis, etc.
AlUger pre\ iously discussed using ultrasound technology to create vaccines in U.S. Pats. Nos 5,582,829 (Alhger) and 6,303, 12Q (Alliger), AHigcr treats substantial K \iab1e cells, bacteria, or \ iiuses (i e. those that are mtact and capable of functioning) with uih abound in order to make a\ ailable antigens capable of inducing an immunogenic and or therapeutic response Specifically, the treatment of cells and viruses with ultrasound is intended to deactivate the potential!) harmful cells and \mises and to also disperse the antigens present for use as a \aceine without fuither processing.
ALHgci recommends that the procedure is conducted at ioom tempeurture whiie maintaining the temperature of the sample containing the microbe against which a vaccine is developed between zero and 5 degrees Celsius. The minimization of heat is to pie\ent the den aiming of the antigens. Denatuiating these antigens v ould limit theif ability to produce a specific immune response, thus diminishing the potential immunogenic effect of the \accine Λlliger method is to delher ultrasound at a specific frequency , intensity, and dutatkm in ordei to rupture and destroy the viruses and bacteria within the sample through cavitation, to disperse the available antigens, and to do so without iaistng the temperature of the \ iruses or bacteria to a level that would denature the antigens
Aihgei iurther states that the time must be sufficient to disrupt the vύuses or cells so that no \ irulent cell structme remains, to do this. Λihger states that one gsam of cultured cells may generally tequire about 3 minutes of sonication
Λs for sonicating the \ iruses and cells, Ailiger delivered ultrasonic \va\es to the microbe sample through a liquid medium at a frequency of about 20 kHz to about 40 kHz. He stated that abøxe this frequency range cav itation intensity is reduced considerably, even at high power inputs, so that cells or viruses may not be fully disintegrated ΛIHger specifically stated that the minimum intensity of the sonic waves should be about i w att sq. cm, and that the preferable intensity level at about 20 kl I/ is 50 to 175 watts sq cm
ΛIHger failed to mention the role of using different ultrasound parameters and additional factors such as the volume of the sample solution containing microorganisms and the geometrical shape of the ultrasound tip and vial container to be used to achieve the most efficient iesults in uitiasomc vaccine development. Because of the shortcomings of the classical approaches and ASJigei's approach, there is still a need for apparatus and methods that can produce inactiλ ated \ acchies that can both produce a stronger immune response and that can produce attenuated micioorgaπisms for \ aecine development incapable of levertmg back to a virulent strain.
SUMMARY OF THE INVENTION
The present hπentioπ is directed towards mφtovements of apparatuses and methods for the creation of \acciαes using ultrasound waves previously researched and tested h\ the author of this patent in the 19S0's. Appaiatus and methods in accordance with the present invention may meet the abo\ e-raeπtioned needs and also pτo\ ide additional ad\ antayes and imρro\ ements that will be recognized by those skilled in the art upon rc\ iew of the present disciosuie.
The present invention comprises an ultrasonic geπcraioi, an uitrasoiuc iransducei, a sonicatton tip, and a \ ial oi container of a solution that can be sonicated to create \ accines. fhe solution contained in the vials is a mass of \ iruses, bacteria, oi othci infectious agents The solution is sonicated with uluasound wa\es to destrov the \ iable infectious \ irus bacterium or infectious agent while also ieleasing the appropriate antigens, thus iesullmg in a vaccine for that virus, bacterium, or other infecrious agent.
Ultrasound waves can be de!i\ered to the solution eithet directly through the insertion of the ultiasound tip into the solution, through a coupling medium, or through an air gas medium The ultrasound tip that is used can vary depending upon the type of delϊ\er> method chosen
There are three different types of recommended methods for sonicating a solution b> the insertion of the ultrasound tip into the solution itself. The first method uses tx special shaped \ iai where the ultrasound tip remains in the same position during the delivery of the ultrasound energy while the last two methods utilize movement of the ultrasound tip during the sonication treatment.
T here are also different types of recommended methods for sonicating the solution through a coupling medium There can be a medium placed between the tip and the \ ml, there can be a liquid medium through which to deliver ultrasound waves, or the \ iai containe* itself can be used as a medium if the tips is pressed up against the v ial/container.
Rased on the ultrasound intensity that is utilized, the sonication time of the solution can vary. However, the intensity of the ultrasound waves can be controlled through a \ ariaiion in the ultrasound parameters such as the frequency, the amplitude, and the treatment time The process may require different intensity levels and ultrasound parameters based on the specific type of virus, bacterium or other infectious agent used to create the vaccine and based on the volume of the solution containing microbes to he sonicated
T he invention is related to the apparatus and methods of deliv ering ultrasound energy to viruses, bacteria, or other infectious agents in order to create a vaccine to treat the virus, bacteuum, oi infectious agent. One aspect of this im ention may be to pro\ sde a method and dev ice foi the creation of different v accines.
Another aspect of the invention may be to pro\ ide a method and dev ice for ihe creation of \ acciπes without the risk of toxicity that occurs with other chemical and tempeiature cieatioa methods Another aspect of the invention ma\ be to pro\ ide a method and de\ ice for the creation of high quality vaccines
Another aspect of the indention may be to pan ide a method and device i'oi the improvement of \ accine creation methods without using temperature or chemical influences Another aspect of the invention may be to pro\ ide a method and de\ ice for the creation of vaccines vuth a decreased production time
Λnothei aspect of the invention mas be to pro\ ide a method and de\ ice for the continuous production of vaccines
Another aspect of the invention may be to pro\ ide a method and de\ ice for the mass produc αon of \ acci ries
These and other aspects of the invention will become more apparent from the v> utters descriptions and figures below .
BRII' F DHSC 1RIR ION Oi* '1 HV SlRAW INCSS
The present Invention will be shown and described with reference to the drawings of preferred embodiments and clearly understood in details
Figure 1 is a perspective \ lew of an ultrasound \accme development system where the ultrasound tip is inserted into the solution.
Figure 2 is a cross-sectional view of an ultrasound tip connected \ia a coupling medium to a \ ial
Figure 3 is a cross-sectional view of an ultrasound tip inserted into a liquid bath with a vial also inserted into the bath to delπcr ultrasound energy through the liquid to the vial. Figure 4 is a cross-sect son a 1 \je\s of an ultrasound tip inserted into a vial but located at a distance from the solution in the vial.
Figure 5 are cross- sectional views of example ultrasound tips for use in the ultrasound \ accine development <.) steιn.
Figure 6 are cioss-seetional \ iews of example different shaped \ ials foi use m the ultrasonic vaccine development s\ stem where the tip is inserted directly into the solution and sonicates the solution from a constant position
Figure 7 is a cross- sectional \ie\\ of recommended sonication methods to use with the ultrasound vaccine de\elopment system wheie the tip is insetted into the solution nnά moxes during sonication Figure 8 is a cross-sectional view of a production- tine method to use with the ultrasound \ accine development system
Figure 9 is a cross-sectional \iew of a eaiousel method to use with the ultrasound vaccine development system. DETAILED DESCRl PTK)N OF THE INVEN TION
The present invention is an apparatus and methods for the development of vaccines using ultrasound technology. Preferred, embodiments of the present invention in the context of an apparatus and methods are illustrated in Ui e figures and described in detail below. Fig, 1 illustrates the vaccine creation apparatus that has an ultrasonic generator 1. an ultrasonic transducer 2, a sonication tip 3. and a via! 4 or other container in which a solution vviil be placed. The solution in the vial or container is a mass of viruses, bacteria, or other infectious agents. The solution is sonicated with ultrasound waves to destroy the viable infectious vims, bacterium, or other infectious agent while aiso releasing the appropriate antigens, thus resulting in a vaccine against that virus, bacterium, other infectious agent. Because the resulting vaccine is available for immediate use, the production time of vaccines developed through this method is lower than the production time of vaccines developed through classical methods mentioned above.
Ultrasound waves can be delivered to solution either directly through the insertion of the ultrasound tip into the solution Fig. 1 , through a coupling medium adjacent to the vial Fig. 2 or near the vial Fig. 3, or through the air or gas medium Fig. 4.
Fig. 5 shows examples of recommended ultrasound tips that can be used depending on the type of delivery method. Fig. 5a is a spherical ultrasound tip 13 and Fig. 5b is a spherical ultrasound tip 14 that contains a centra! orifice 15. Figs. 5c/5d/5e/5f show ultrasound tips with a flat radiation surface. Figs. 5c and Se are ultrasound tips 16 and I? with a fiat radiation surface, and Figs. Sd and 5f are ultrasound tips 17 and 20 with flat radiation surfaces and central orifices 18 and 21. Figs. 5g and 5h show ultrasound tips 22 and 23 with a curved radiation surface - Fig. Se shows an ultrasound tip 23 with a curved radiation surface mid a central orifice 24, The central orifices of the ultrasound tips shown in Fig. 5 can be used to deliver solution into a vial or container and/or can be used to provide sonication during or after delivery of the solution.
Fig. J shows direct sonication where the ultrasound tip 3 is inserted into the vial 4 and into the solution - the recommend tip 3 to use is either a sphere Figs, 5a/5b, a flat radiation surface Figs. 5c/5d/5e/5f, a rectangular prism (not shown), or another similar shape or combination of shapes, with the sphere Figs. 5a/5b as the preferred tip. The most preferred tip is the spherical tip 14 that contains a central orifice 15; this is because the most preferred treatment method m\ ol\ es the use of a sphencai sonication tip ^heie the solution is delr\ered into the \ mi or container through the centra! orifice
Fig. 2 shows deb\ci\ of ultrasound energv fiυm an uiUasound tip 5 thiough a coupling medium 6 such as liquid gel, ot the glass plastic Λ ial 7, v*heie the tip 5 is pressed up against the S \ m\ 7 or container — the lecommendcd configuration of tip 5 is one that matt he** the shape of tip 5 to the geometric shape of the \ ml 7 or contamei l<or example, if a sphencai \ia1 is to be sonicated the recommend tip would be a curved-shape tip (not shown) t»o that the tip would fit atound the shape of the \ ial
Fig. 3 show s deb\ er> of ultrasound energv ftorø an ultiasound tip 8 thiough a liquid !0 medium 9 where the ultiasound Up 8 JS located at a dϊ&tance from the \ ial 10 -the recommended up to use is a Oat shaped tip Fig. 5c/Fig. 5d w nh the prefcucd tip being a flat shaped tip without a central office as depicted m Fig. 5c. Foi this method, the ultiasound tip 8 is. placed into the liquid medium 9 and delrveis ultrasound eneigx to the ual lθ thtough the liquid medium 9
FIg. 4 show s delrv er> of ultrasound energv fiorø m\ ultiasound tip 1 1 to a \ial Ϊ2 thiough 1 ^ an ait or gas medium - the recommended tip to use is a flat-shaped tip Fig. 5c/5d/5e/5f, w Uh the pielened tip eitheϊ Fig. 5c oi 5c Foi ώis delneiy method the ullrasomid tip 1 ϊ is inserted into the \ ial 12 but the tip 11 does not come into contact \\ ith the solution m the \ml 12,
Fig. 1 shows delncix of ultiasound eneig\ where the ultrasound tip 3 is inserted into the viai 4 and into the solution there are three different ts pes of recommended methods for this 0 direct somcatioα Fig. 6 show s the first method that uses a special shaped \ sal wha e the ultrasound tip temaπis m the same position duπug the delnerv of the uliiasound eneigv while Fig. 7 s!κnvs the last two methods that utilize moxement of the ultrasound tip during the somcation treatment
Fig. 6 shows the fust method of duect somcation that uses both a special shaped \ ial 26 5 28, oi 30 and a corresponding ultrasound tφ 25, 27, oi 29 that mmois the shape of the \ iai 26 28, or 30 Theie aie thiee dsffeieπf jetυmniεnded shapes oi \ials 26 28, OΪ 30 to use w ith a couc&pondmg ulua&ound tip 25, 27, or 29 the three bhapcs aie Fig, 6a a spherical \ tal 26, Ftg. 6b a tectangulai \ial 28, and Fig. 6c a cuned \ia! 30 With the sphencai Ma! 26 shown in Fig, 6a a spherical shaped ultiasound tip 25 is inseited into the bortom of the \ ial 26 Because the ^O ultrasound tip 25 mπrors the shape of the ual 26, there is an equidistant space between the uhτasound Up 25 and the vial 26; this allows for the solution to be sonicated equaik, thus resulting in an effective \ acciiic creation This same concept of equal sonication also applies to the rectangular shaped \ial 28 shown in Fig. 6b. Λ rectangular-shaped ultrasound tip 2? that mirrors the shape of the vial 28 is inserted into the solution, therefore causing the solution to be sonicated equally Finally, the cun ed shaped ultrasound tip 29 show n m Fig, 6c can be inserted into a curved shaped vial 30, therefore allowing for equal sonication of the solution contained in the via! 30 1 he shapes of the vials 26, 28, oi 30 contained m Fig. 6 ate the recommend shapes, and the prefeired shape is the spherical \ ial 26, other similar shapes or combinations of shapes of \ ials and ultrasound tips can also be utilized Fig. 7 shows the second potential method of direct sonicaiion where the ultrasound tip 31 is inserted uno the bottom of the via! 32 containing the solution and then the tip rises in a continuous motion 33 as it delivers ultrasonic energy After the sonication begins, the ultrasound tip 31 gradually rises to the top of the solution while delivering ultrasound energy The ultrasound tip 31 stops its movement and stops delivering ultrasound energy after it reaches the top and the entire solution has been sonicated This movement during the delivery of ultrasound energv allows for equal sonication of the entire solution, which is effective because it ensures that the harmful cells and viruses are destroyed to prevent toxicity and that the antigens are released. This is more effective than inserting the tip to the bottom of a regular shaped \ial and attempting to sonicate the entire solution from one position - delivering fiorn one position results in \arying sonication because the distance of the solution to the ultrasound tip varies throughout thc \ial.
Fig. 7 also shows the third potential method of direct sonication wheie the ultrasound tip 31 is inserted into the bottom of the vial 32 containing solution and the tip 31 rises m a step- mode motion 34 Sonication occurs for a brief time and then stops. The ultrasound tip 31 is moved slightly higher, and then sonication occms again. This step-delhery motion 34 is repeated until the tip 31 has mo\ ed to the top and the entire solution has been sonicated Simiiarh to the continuous movement deli\er>, this method allows for equal sonication of the entire solution This distance between delneπ steps in this step-mode delivery- method can be of equal or v arying distances Fig, S shows a cross-sectional \ie\v of a production- Hoe somcation method to use \v ith the ulttasound vaccine de\ elopment system Y ials 38 men e down the product ton line towards tiie ultrasound tip 3$. I 'port reaching the tip 35, the tip 35 mo\es down 37 into the \ ial 36 to sonicate the solution contained in the vjal 36, After sonication, the ultrasound tip 35, mo\ es back up 37 and warts until another \ Ia! 38 moves to the ultrasound tip 37. This process is repeated to sonicate multiple \ iais 38. There are multiple options in which the solution can be inserted m the \ sals 38, Pre-filled vials 38 can be placed on the line, the ultrasound tip 37 can fill the % ial 36 v, ith the solution tluough a central oullce (not shown) m the ultrasound tip 37, or there can be a separate delivery mechanism source or sources (not shcπui) that can till the \ sals 38 as they mo\ e down the production line and towards the ultrasound rip 35. I here are also multiple versions of the system that can be used - besides using different methods of filling the \ials with solution, one or more ultrasound lips can deliver ultiasonic cnctgy to one ot moiε \sals at a time. Furthermore, different methods of direct sonication where the ultrasound tip is inserted solution can also be used as described abcn e Hg, 9 is a cross-sectional \ iew of a carousel somcation method to use uith the ulltasound vaccine development s> stem. Vials 42 are placed in the carousel system and rotate around the caiousel until they reach the ultrasound tip 39 When the \ ial 40 readies the ultrasound tip 39, the tip 39 mo\ es down 41 into the vial 40 to sonicate the solution contained in the vial 40. After sonieauoπ, the ultrasound dp 39, rames back up 41 and wails until another \ ial 42 moves to the ultrasound dp 39. This process is repeated to sonicate multiple vials 42 1 here are multiple options in which the solution can be inserted m the \ tals 38. Pre-filled vials 42 can be placed in the carousel, the ultrasound rip 39 can fill the \ial 40 with the solution through a central orifice (not shown) in the ultrasound tip 39, oi there can be a separate delivery mechanism/source oi sources (not shown) that can fill the \ ials 42 as they rotate around the caiousel and towards the ultrasound tip 39, Furthermore, different methods of direct sonication where the ultrasound tip is inserted solution can also be used as described above The pioductioπ line method and the carousel method are only recommended systems to sonicate \ ials of solution. Additional methods and systems can be similar IY effective
Based on the ultrasound intensity that is utilized, the son teat ion time of the solution can be from fractions of a second and above for both pulse and continuous waxe mode delnery. Ilowe\cι, the intensity of the ultrasound waves can be controlled through a variation in the
1 ! ultrasound parameters suck as the frequency the amplitude, and the treatment time. The recommended frequency iange for the ultrasound wa\es is Ϊ6 k!ϊ/ to 20 MI i/. with the pretested frequency range of 30 kHz 120 kH?, and the most preferred frequency \aiue is 50 kHz, The amplitude of the ultrasound waves can be 2 microns and abo\e. with the recommended amplitude to be in tange of 3 microns to 250 miaous, and the most preferred amplitude value is 8(3 microns. The recommended sonication treatment time is 5 10 seconds. Hie amount of solution in the \ ial is at least 1 grams, and the pieferred amount of solution is 5 IO grains.
The process may requiie different intensity levels and ultrasound parameters based on the specific type of \irus, bacterium, or other infectious agent used to create the vaccine and based on the amount of the solution to be sonicated ljor example, 5 ml of a solution can be sonicated with an ultrasound frequency of 50 kHz. an amplitude of p-p 50 microns, an ιnlensιt> of about ϊflOO watts cm2, and the sonication time will take up to 10 seconds based on the type of virus, bacterium, etc solution The longer the sonication time of the solution, the lower the level of intensity is required; the shorter the sonication time, the higher die lev el of intensity is required, The sonication of the solution can be conducted tn drffeient temperature ens tronmems. but the preferred method is to use roorø temperature.
Although specific embodiments and methods of use have been illustrated and described herein, it w ill be appreciated by those of oidinarv skill in the art that an> arrangement that is calculated to achieve the same purpose may be substituted foτ the specific embodiments and methods shown It is to be undeistood that the above description ts intended to be illustrative and not restrictive. Combinations of the above embodiments and other embodiments as well as combinations of the above methods of use and other methods of use will be apparent to those having skill in the art upon review of the present disclosure. The scope of the present invention should be determined with reference to the appended claims, along with the full scope of equi\ alents to which such claims ate entitled.

Claims

CLAIMS 1 claim,
1 ) A method for creating vaccines for viruses, bacteria, or other infectious agents by using ultrasound technology, comprising the steps of a) delivering ultrasonic ener»\ to a wai or container of a solution, where the solution is a mass of \ iruses. bacteria, or othei infectious agents, b) v\ herein the deli\ eiy of ulttasonic energy is either through the diiect imei lion of the ultrasound tip into the solution, through an air or gas medium, or through a coupling medium such as a liquid, a gel. or the glass plastic \ ial, and i) wheicin the ultrasound energy has an intensity capable of fully destroying the \iable
\ irus, bacterium, or other infectious agent contained in the solution; ii) wherein the ultrasound energy has an mtensiU capable of partially destroying the \ iable virus, bacterium, or other infectious agent contained in the solution. in) wherein the ultrasound energy has an intensity capable of releasing the appropuate antigens, tints resulting in a \ accine for that \ irus, bacterium, or other infectious agent, or h ) wheiem the ultrasound eneigy is capable of decreasing the ptoduetion time for a \ accine
2) The method according to claim L further including the step of generating the ultrasonic energy with particular ultrasound paiameteis tπdicam e of an intensity capable creating a
\ accine
3) The method accoiding to dasm 1 , wherein the particular amplitude is at least 2 microns.
4) I he method according to claim 1 , w herein the preferred particular amplitude ss m the range of 3 mic roαs 250 microns. 5} The method according to claim 1. wherein the most preferred paiticulai amplitude value is 80 microns it) The method according to claim 1 , wherein the frequency is in the range of 16 kHz-20 MHz 7) T fie method according to claim 1. wherein the piefeπed frequency is in the range of 30 kHz- 120 kϊi/
8) I he method according to clasro I , v\ herein the most prefei red frequency value is 50 Id ϊ/.
< L>. ) T he method according to claim I , vvheiein the ulttasonic energy is delivered for a duration of fractions of a second and atκn e. i 0)The method according to claim S . wherein the ultrasonic cnoigy is delivered for a preferred duration of 5 10 seconds i 1 )1 he method according to claim L wherein the amount of the solution contained in the vial is at least ! grams 12) The method according to clasro 1 , wherein the preferred amount of solution contained in the \ials ΪS 5 10 grams.
IJ) I he method according to claim L wherein the preferred step of delivering ultrasonic energy includes the step of providing means for delivering the ultrasonic energy by inserting the ultrasound tip into the solution. 14) fhe method according to claim 10, wherein the step of delivering ultrasonic cnergs is achiex ed by continuous mo\einent of the ultrasound tip m the solution, whereby the ultrasound tip is inserted into the bottom of the solution, sonication begins, the ultrasound tip rises to the top while delivering ultrasonic energy, and the ultrasound tips stops both moving and delivering ultrasonic energy to the solution after ultrasound reaches the top and after the ultrasound tip has sonicated the entire solution
15) T he method according to claim 10, wherein the step of delivering uJtsasomc energy is achieved by a step-mode delivery method of the ultrasound tip, wherein the ultrasound tip delivers ultiasound energy, stops, and then moves up to debx ei ultrasound energy again, and this process of step-mode delivery is repeated until the whole solution has been sonicated Ki) The method according to claim 10, wherein the step of delivering ultrasonic energΛ is aciiie\ ed by the ultrasound tip being held m a constant position
17) I he method according to claim 13. w herein the shape of the ultrasound tip mirrors the shape of the wάl in which the tip is inserted 18>The method according to claim 1. wherein the step of delh ering υlnasonic energy includes the step of providing means for delivering the ultrasonic energ} through an air or gas medium.
19) The method according to claim 1. wherein the step of delivering ultrasonic energy includes the step of providing means for delivering the ultrasonic energy through a coupling medium such as a liquid, a gel. the glass/plastic \ iaL etc.
20) The method according to claim 16, wherein the shape of the ultrasound tip mirrors the outside shape of the \ iai in which the tip contacts so that the whole tip is in contact with the \ial either directly or through a coupling medium. 21 } The method according to claim i . wherein the ultrasonic energy destroys the viable viruses, bacteria, or other infectious agents in the solution, releases the antigens of the uruses, bacteria, or other infectious agents in the solution, resulting in the creation of a \acciae with a decreased production time,
22) An apparatus for creating vaccines for viruses, bacteria, or other infectious agents by using ultrasound technology, comprising- a) a generator and a transducer for generating ultrasonic energy; b) wherein the transducer tip cielήers the ultrasonic energy to the solution; and i) wherein the ultrasound energy has an intensity capable of full ^ desπoj ing the \ table virus, bacterium, or other infectious agent contained in the solution; ii \ wherein the ultrasound energy has an intensity capable of partially destroying the viable vims, bacterium, or other infectious agent contained in the solution, iii) wherein the ultrasound energy has an intensity capable of releasing the appropriate antigens, thus resulting in a \ accine for that \irus, bacterium, or other infectious agent; or iv) wherein the ultrasound energy is capable of decreasing the period tirøe from when the solution is sonicated until the vaccine is available for use.
23) "I he apparatus according to claim 22. wherein a carousel holds the \ials of solution to be sonicated. 24} The apparatus according to claim 23, wherein pre-11 lied \ ials of solution aie placed into the cat ousel
25) I he appaiatυs according to claim 23. wherein solution is inserted into the \ ιai& through an oiifice in the ultiasound tip 26} The apparatus according to claim 23, wherein solution is inserted into the \ ials through a separate de liven' mechanism/source oi sources in the cai ousel
27} The apparatus according to ciaun 23, wheiein an ultrasound tip oi tips delivers ultrasonic energy to one or more vials of solution at a time, and the carousel rotates after each delhery of ultrasonic energy so thai all \ ials can be sonicated 28} I he apparatus according to claim 22, wherein the \ ials ase placed into in a product! on- line.
29} I he appaiatus according to claim 28, w herein pre-fHied Λ ials of solution are placed into the production-line
30} The apparatus according to claim 28, wherein solution is inserted into the \ials through an orifice in the ultrasound tip. 31 ) f he apparatus according to claim 2S, wherein solution is inserted into the v ials through a separate delh ery mechanism souice or sources tn the production-line
32} I he appaiatus according to claim 28, whet em an ultrasound tip or tips delivers ultrasonic CfJCi gy to one or more \ ials of solution at a time, and the production line moves after each delis ery of ultrasonic energy so that all v ials can be sonicated 33 ) The apparatus according to claim 22, wheiein die generator and transducer generate the acoustic energy with particulai ultrasound parameters indicatixo of an intensity capable of ci eating a vaccine
34} The apparatus according to claim 22, wherein the particular amplitude is at least 2 microns,
35} I he apparatus according to claim 22, wherein the preferred particular amplitude is in the i ange of 3 microns 250 microns
36} The apparatus according to claim 22, wherein the most prefeπed particular amplitude value is 80 microns
H> 37} The apparatus according to claim 22, wheietn tlie frequenc> is in the range of 16 kHz~20 Mil/
38) I he appaiatus accoidiπg to claim 22. wherein the piefeπed frequency is m {he range of 30 kHz- 120 LHz 39} The apparatus according to claim 22, wherein the most preferred frequency \ alue is 50 kHz
40) The apparatus according to claim 22, wheiein the uitiasonic energy is delneted foi a duration of fractions of a second and abcne
41 )1 lie apparatus according to claim 22, wheie the ultrasonic energ\ is delivered for a preferred duration of 5 - 10 seconds 42) The appaiatus according to claim 22. wherein the amount of ihe solution contained In the uals is at least 1 grams
43) I he method according to claim 22. wherein the pieferred amount of solution contained in the \ iaSs is 5 10 grams.
44) I lie apparatus accoiding to claim 22, wheiein me tiansducer contains a iadianon suiface ha\ ing a surface area dimension ed constructed for achie\ ing deln crv of the ultrasonic energy to the solution with an intensity capable of cteatnig a \accine
45) I he appaiams according to claim 22, v\heτem the transducer contains a radiation surface where the shape of the iaduitioii surface is either a sphere, a tectaiigitlat piistii, a Hat suiface, a cuned suiface, ot anothei comparable shape ot combmanon of shapes. 46 ) Hie apparatus according to claim 22, wheiein die transducer contains a radiation surface intended to achie\ e deiivcsy of the ultrasonic energs to the solution with tin intensin capable of eteating a \accme
47} The apparatus according to claim 22, wherein the shape of the peripheral bonndan of the radiation surface is cither circular, polygonal, or another comparable shape or combination of shapes
48) The apparatus according to claim 22, wherein the shape of the peripheral boundary of the iadiation surface ΪS intended to achieve deineiy of the ultfa.sonie en erg v io the solution with an intensity capable of creating a \accine 49}The apparatus according to claim 22, wherein the tiansducer includes a jadiation suiface. a selection is made of a si/c and of a surface aiea of the radiation surface, a shape of the peripheral boundary of the iadiaticm surface that is circular, polygonal, or another comparable shape or combination of shapes, and a shape of the radiation surface that is either a sphere, a rectangular prism, a flat suitace, a cun ed surface, or another comparable shape or combination of shapes, and the particular ultrasound parameters of the generated ultrasonic energy fot achieving delivery of ultrasonic energy to the solution with an intensit) capable of creating a \accine
50} The apparatus according to claim 22, wherein the shape of the ultrasound tip mirrors the shape of the \ ial in which it is inserted
5 U The apparatus according to claim 22, wherein the ttaπsducer is driven by a continuous, pulsed, or modulated frequency,
52) The apparatus according to claim 22, wherein the drπing wave form of the transducer is selected from the group consisting of sinusoidal, rectangular, trapezoidal and triangular wa\e foims.
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US7842249B2 (en) 2010-11-30
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US20070231346A1 (en) 2007-10-04
US20080095799A1 (en) 2008-04-24
CN101553250A (en) 2009-10-07
US7943352B2 (en) 2011-05-17
WO2007117964A3 (en) 2009-01-29
JP2009531454A (en) 2009-09-03

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