Methods for drying a viral vaccine

A viral vaccine in the dried state is described. Methods for drying viral vaccine in the liquid state into viral vaccine in the dried state are presented. The methods may include introducing the viral vaccine in the liquid state into a gas stream and recovering viral vaccine in the dried state from the gas stream.

FIELD OF THE INVENTION

The present inventions relate to viral vaccines and, in particular, to methods and apparatus for the production of dried viral vaccines.

BACKGROUND OF THE INVENTION

Viruses are the source of diseases and other health issues faced by the world's human and animal populations. A wide variety of viral vaccines have been developed to protect these populations. Viral vaccines can include live viruses, attenuated viruses, subunits of viruses, and/or individual molecules to confer protection against a viral infection. Typically, the viral vaccines include at least a portion of the viral particle to induce the recipient of the viral vaccine to develop antibodies against the viral particle to prevent later infection. Viral vaccines have protected large segments of the world's population from infection by viruses. However, viral vaccines are frequently expensive and/or difficult to produce and process on large scales. Therefore, a need exists for apparatus and methods that improve various aspects of viral vaccine production.

Many viral vaccines can be needed cyclically, such as for example the influenza viral vaccines which are typically required annually before the flu season. Because production can take a considerable amount of time, it can be desirable to produce and store viral vaccine many months before it is needed. However, many viral vaccines can lose efficacy if stored in a usable formulation for a period of months. Therefore, many viral vaccines are dehydrated prior to storage to increase their shelf life and then resuspended prior to use.

Various processes have been used to dry viral vaccines. These processes are typically relatively inefficient and time consuming. The inefficiency and time make the end product more expensive. Further, current processes do not typically permit the continuous production of dried product. This can further increase the cost and time for production of a viral vaccine. Therefore, the need exists for apparatus and methods that may more quickly and efficiently prepare a viral vaccine for storage.

In one prior methodology, viral vaccines can be dehydrated by freeze drying. Freeze drying (also known as lyophilization) is a dehydration process that typically involves freezing the liquid viral vaccine and then reducing the surrounding pressure to sublimate the frozen water into the gas phase, which may be evacuated. After the frozen water has been sublimated and the water vapor evacuated, the end result is a viral vaccine in the dried state.

The process of producing dried viral vaccine by freeze drying typically includes several steps. The process typically begins by placing liquid viral vaccine within one or more vials, with the one or more vials being unsealed. The liquid viral vaccine within the one or more vials is then subjected to the freeze drying process resulting in one or more vials containing dried viral vaccine. After the freeze drying process is complete, the one or more vials may then be exposed to a sterilizing gas and then sealed in vacuum conditions. This results in one or more vials containing sterile dried viral vaccine. Alternatively, following freeze drying, the vials may be sealed and the sealed vials exposed to a radiation source for sterilization. Freeze drying viral vaccine may be a time consuming and energy inefficient process. Freeze drying is typically a batch type process where the liquid viral vaccine in groups of vials is subjected to the freeze drying process. Therefore, a need exists for more efficient methods for producing dried viral vaccine.

SUMMARY OF THE INVENTION

Methods and compositions in accordance with the present inventions may resolve many of the needs and shortcomings discussed above and will provide additional improvements and advantages, including faster and more efficient drying, larger batch sizes, higher viability and/or higher antigenic potency, longer shelf life in the dried state, and other properties.

The present invention is based on a variety surprising discovery that viral vaccines can be dried in a gas stream at very high temperatures, such as about 1000° F. and still retain viability and/or antigenic properties.

The present invention provides viral vaccines in the dried state produced by pulse combustion and methods for producing viral vaccines. In various aspects, the dried viral vaccine produced by pulse combustion may have one or more of the following properties: (1) particle size between about 1 and about 100 microns, (2) viral particle viability greater than about 30%, and preservation of antigenicity, (3) moisture content between about 0.5% and about 10%, (4) shelf life of greater than 12 months.

The viral vaccine in the dried state is formed by vaporizing the liquid medium in which the viral particles are suspended, using a gas stream. The gas stream has at least a certain velocity and/or a certain temperature selected to vaporize the liquid medium. The characteristics of the gas stream are selected to vaporize the liquid medium while retaining the ability of the viral particles to elicit an immunogenic response when administered as a vaccine.

The present invention may also provide methods for drying viral vaccine in the liquid state into viral vaccine in the dried state. The method may include the step of introducing the viral vaccine in the liquid state into gas stream. The methods may include the step of recovering the vaccine in a dried state from the gas stream.

In some aspects of the invention, the gas stream is a pulsed gas stream. The gas stream may have an inlet or first temperature and an outlet or second temperature. The first temperature of the gas stream may range from about 700° F. to about 1300° F., or from about 750° F. to about 1000° F. The second temperature of the gas stream may range from about 135° F. to about 250° F. The frequency of pulses of the gas stream may range from about 30 to 1000 Hertz.

In some embodiments, the viral vaccine introduced into the gas stream comprises an attenuated virus, killed viruses, viral components or combinations thereof.

The invention also provides a viral vaccine in a dried state, wherein the vaccine is dried by introducing the viral vaccine in the liquid state into gas stream and recovering the vaccine in a dried state from the gas stream. The gas stream may have an inlet or first temperature and an outlet or second temperature. The first temperature of the gas stream may range from about 700° F. to about 1300° F., or from about 750° F. to about 1000° F. The second temperature of the gas stream may range from about 135° F. to about 250° F. The frequency of pulses of the gas stream may range from about 30 to 1000 Hertz.

In some embodiments, the viral vaccine in a dried state comprises an attenuated virus, killed viruses, viral components or combinations thereof.

Other features and advantages of the inventions will become apparent from the following detailed description and from the claims.

All Figures are illustrated for ease of explanation of the basic teachings of the present inventions only; the extensions of the Figures with respect to number, position, order, relationship and dimensions will be explained or will be within the skill of the art after the following description has been read and understood. Further, the apparatus, materials and other operational parameters to conform to specific size, dimension, force, weight, strength, velocity, temperatures, flow and similar requirements will likewise be within the skill of the art after the following description has been read and understood.

Where used to describe the drawings, the terms “top,” “bottom,” “right,” “left,” “forward,” “rear,” “first,” “second,” “inside,” “outside,” and similar terms may be used, the terms should be understood to reference the structure and methods described in the specification and illustrated in the drawings as they generally correspond to their with the apparatus and methods in accordance with the present inventions as will be recognized by those skilled in the art upon review of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term, “animals” refers to all members of the kingdom animalia, including humans.

The present invention provides methods for removing liquid medium from viral vaccines. As used herein, viral vaccines include a liquid medium and one or more types of viral particles from one or more types of viruses. The invention also provides dried vaccines produced using a heated and/or pulsed gas stream. The apparatus typically includes a dryer to produce a gas stream to remove the liquid medium suspending the viral particles in the viral vaccine. In one aspect, the liquid medium is vaporized by a gas stream and the viral particles are left in a condition to elicit an immune response when administered as a vaccine. The gas stream may be heated and/or pulsed.

The Figures generally illustrate various exemplary embodiments of apparatus and methods including aspects of the present inventions. The particular exemplary embodiments illustrated in the figures have been chosen for ease of explanation and understanding of various aspects of the present inventions. These illustrated embodiments are not meant to limit the scope of coverage but instead to assist in understanding the context of the language used in this specification and the appended claims. Accordingly, variations of the apparatus and methods for dehydrating viral vaccines different from the illustrated embodiments may be encompassed by the appended claims.

Viruses for viral vaccines73are typically commercially produced by host cells supported in a growth medium. After a sufficient number of virus have been produced by the host cells, the virus is separated from the growth medium and remaining host cells and cell components. The virus may also be manipulated to inactivate it or to separate out desired portions or components of the virus to be administered to a patient. The virus or viral particles are then resuspended and may be concentrated in a liquid medium. The viral particles suspended in a liquid medium may constitute a viral vaccine73.

The viral vaccine73is in a liquid state75when the viral particles78are suspended in the liquid medium. The viral vaccine73includes viral particle78, which may include live or attenuated virus, portions or components of the virus and/or material derived from the virus configured to produce an immunologic response in the recipient to one or more pathogens. In some aspects, the viral particles78include killed virions. In other aspects, the viral particles78include live attenuated virions. In still other aspects, the viral particles78include various subunits of virions such as, for example, at least portions of the genome, at least portions of the capsid, or at least portions of the envelope, or combinations thereof. The viral particles78may be configured from virions in other ways and include other material or materials derived from the virions as would be recognized by those of skilled in the art in the art upon review of this disclosure.

The viral vaccine73in the liquid state75may be generally in a liquid form, or may be in the form of slurry, paste, or other viscous or non-Newtonian form. The viral vaccine73in the liquid state75may include various agglomerations, aggregations, non-homogeneities and/or clumps. The viral vaccine may also include adjuvants and other components known to the skilled artisan. When the liquid medium is water or otherwise aqueous, the moisture content of the viral vaccine73can be between 0.5% and 10%. In one embodiment, the moisture content is around 7% to 9% when the viral vaccine73is in the dried state77. In accordance with aspects of the present invention, the liquid medium is removed from viral vaccine73by a gas stream20. The removal of the liquid medium can allow for more prolonged storage of the viral vaccine73. At least some of the ability to elicit an immune response of the viral vaccine73in the liquid state75is preserved when the viral vaccine73is dried from the liquid state75to the dried state77by the gas stream20. Prior to administration, the viral vaccine73is typically resuspended. Upon administration, the resuspended viral vaccine is formulated to elicit an immunologic response in the recipient. The recipient may be a human being or an animal.

The viral vaccine73in the liquid state75may include water, and may include various acids, bases, and/or buffers to control the pH. Other non-aqueous solvents may also be included in the viral vaccine73in the liquid state75and various preservatives may be included in the viral vaccine73in the liquid state75. In some embodiments, the viral vaccine73in the liquid state75may include a carrier material79with the carrier material79configured to form a portion of the viral vaccine73in the dried state77when the viral vaccine73in the liquid state75is dried into viral vaccine73generally in the dried state77. The carrier material79may aid in the preservation of the viral particle78in the dried state77. The carrier material79may provide bulk to the viral vaccine73in the dried state77, and may assist in maintaining the activity of the viral vaccine73in the dried state77. The carrier material79may be, for example, a sugar or combinations of sugars such as, without limitation, glucose, lactose, maltose, dextrose, fructose, mannose, xylose, ribose, cellobiose, raffinose, trehalose, maltodextrin or combinations thereof. The carrier material79may be protein or other carrier material,79, such as, without limitation, 6-amino mannose, mannitol, sorbitol, glycerol, polyethylene glycols, maltotriose, dextran, maltodextrins, cellulose, aminoglycosides, amino acids, such as betaines, prolines, glycine arginine, lysine, alanine, sweet whey solids, albumin, polyvinyl alcohol, creatine, nonfat dry milk, polydextran, partially hydrolyzed starches, collagens, gelatins and combinations of materials as would be recognized by those of ordinary skill in the art upon review of this disclosure.

The activity of the viral vaccine73in the dried state77may be defined in various ways. As examples, the activity of the viral vaccine73may be defined as the ability of the viral vaccine73to induce an immunologic response in a recipient. In aspects wherein the viral particle78includes live attenuated virions, the activity of the viral vaccine73in the dried state77may be defined as the portion of virions in the viral vaccine73in the liquid state75that survive the drying of the viral vaccine73into the dried state77. In aspects wherein the viral particle78includes subunits of the virions, the activity may be defined as the portion of the subunits unaltered in, for example, molecular structure and/or orientation after the viral vaccine73in the liquid state75is dried into the viral vaccine73in the dried state77.

The viral vaccine73may be dried from the liquid state75to the dried state77by introducing the viral vaccine73generally in the liquid state75into a flowing gas stream20and recovering the viral vaccine73in the dried state77from the gas stream20. The viral vaccine73is dried as the viral vaccine73is convected along portions of the flow path90by the gas stream20. The viral vaccine73in the dried state77is drier than, and may be substantially drier than, the viral vaccine73in the liquid state75. In some aspects, substantially all of the water may be removed from the viral vaccine73in the dried state77, while, in other aspects, the viral vaccine73in the dried state77may retain some residual amount of water. The water content of the viral vaccine73in the dried state77may be less than 8%. Water, as used herein, may include, for example, water, water in combination with various acids, bases, and buffers, and water in combination with other solvents and additives, and other solvents and volatiles.

In some aspects, the gas stream20may consist generally of air and combustion products produced by the combustion of various solid, liquid, or gaseous fuels or combinations thereof. Examples of fuels would include propane, natural gas, and kerosene. In other aspects, the gas stream20may consist of heated air propelled by the release of compression. In various aspects, the gas stream20may include other gases or combinations of gases, which may be heated in various ways and configured to form the flowing gas stream20, as would be recognized by those of ordinary skill in the art upon review of this disclosure.

In some aspects, the gas stream20may be characterized by a generally continuous flow. In other aspects, the gas stream20may be pulsed, and the pulses may have a frequency that may range from about 30 Hz to about 1,000 Hz. In various aspects, the gas stream20may include regions of high velocity flow, turbulence, and may include supersonic flows and shock waves. Pressures in the gas stream20may be about 2×104Pa (gage) or more in various aspects. Sound pressures in the gas stream20may fall in the range of about 1100 dB to about 200 dB in various aspects. In various aspects, a swirl component may be induced into the flow of the gas stream20.

The flow of the gas stream20defines a flow path90having a first end94and a second end96with the gas stream20flowing generally from the first end94to the second end96. The first end94of the flow path90may be generally coincident with the location at which the gas stream20is generated. The second end96of the flow path90may be generally coincident with the region from which the viral vaccine73in the dried state77is recovered from the gas stream20and may be defined by various structures configured to recover the viral vaccine73. The viral vaccine73in the liquid state75may be introduced into the gas stream20at an introduction location110, with the introduction location100disposed along the flow path90generally between the first end94and the second end96.

One or more passages120, which may be defined by tubes, channels, pipes, or other structures, with each passage120having one or more passage outlets122adapted for the introduction of viral vaccine73into the gas stream20may be located in the flow path90between the first end94and the second end96, and the location of the passage(s)120in the flow path90defines the introduction location110. Viral vaccine73may be introduced into the gas stream20at the introduction location110through the passage(s)120. Pumps, piping, valves, and other such structures may be provided in various aspects to convey the viral vaccine to the passage(s)120for introduction into the gas stream20at the introduction location110as would be recognized by those of ordinary skill in the art upon review of this disclosure.

The temperature of the gas stream20may be 2,300° F. or more generally proximate the first end94of the gas stream20, which may be excessive for drying viral vaccine73. Accordingly, the temperature of the gas stream20may be controlled, in various aspects, to provide a specific first temperature104generally proximate the introduction location110and a specific second temperature106generally proximate the second end96of the flow path90. The temperature of the gas stream20may be controlled in various aspects to control the first temperature104of the gas stream20generally proximate the first end94of the flow path90where the viral vaccine73in the liquid state75may be introduced into the gas stream20. The temperature of the gas stream20may be controlled in various aspects to control the second temperature106of the gas stream20generally proximate the second end96of the flow path90where the viral vaccine73in the dried state77may be recovered from the gas stream20.

For example, one or more gas flows may be combined with the gas stream20as the gas stream20flows along the flow path90to control, at least in part, the first temperature104of the gas stream20at introduction location110. The one or more gas flows combined with the gas stream20may control, at least in part, the temperature at the second end96of the flow path90. The one or more gas flows combined with the gas stream20may control, at least in part, the temperature variation between the first temperature104and the second temperature106. In various aspects, one or more gas flows may be combined with the gas stream20to provide for the uptake of water vapor and/or for other purposes as would be recognized by those of ordinary skill in the art upon review of this disclosure. In various aspects, conditions at the first end94of the flow path90may be adjusted in order to achieve a specific first temperature104and/or specific second temperature106.

The first temperature104and/or the second temperature106may be chosen depending upon the nature of the viral vaccine73to be introduced into the gas stream20in order to be dried into the dried state77. For example, in various aspects, the first temperature104may be about 1,000° F. while the second temperature106may be about 170° F.

The viral vaccine73may be introduced into the gas stream20at the introduction location110to be exposed to the temperature of the gas stream20while being conveyed by the gas stream20from the introduction location110to the second end96of the flow path90. The viral vaccine73may be exposed to the temperature of the gas stream20for an exposure time that may be on the order of fractions of a second, and, in some aspects, on the order of a millisecond or less. The temperature of the gas stream20may cause water associated with the viral vaccine73to flash into the vapor phase, while the latent heat of vaporization of the water in combination with the exposure time may keep the viral vaccine73generally cool thereby protecting the viral vaccine73from the temperature of gas stream20. Turbulence, high velocities, and/or shock waves in the gas stream20may strip water from the viral vaccine73and may otherwise increase the rate of evaporation of water from the viral vaccine73by various mechanisms. The latent heat of evaporation of the water may also cool the gas stream20, at least in part, from the first temperature104to the second temperature106, so that the water content of the viral vaccine73in the wet state75may, in some aspects, control the second temperature106and may control the temperature variation between the first temperature104and the second temperature106, at least in part. The rate at which viral vaccine73in the liquid state75is fed into the gas stream20may control the first temperature94, may control the second temperature96, and may control the form of the temperature gradient between the first temperature94and the second temperature96.

A collector60may be positioned about the second end96of the flow path90to recover the viral vaccine73generally in the dried state77from the gas stream20, and the collector60may generally define the second end96of the flow path90. The collector60may be a cyclone, baghouse, screen or series of screens, filter(s), or similar, or combinations thereof configured to capture the viral vaccine73generally in the dried state77from the gas stream20as would be recognized by those of ordinary skill in the art upon review of this disclosure.

A packaging apparatus165, in various aspects, may be configured to cooperate with the collector60. One or more packages170including vials, ampoules, bottles, gas impermeable packages, and other sealable containers and including any necessary sealing materials such as stoppers, rubber and/or synthetic membranes, metal and/or plastic bands, adhesives, and suchlike may be provided as would be recognized by those of ordinary skill in the art upon review of this disclosure, with the package170defining a package interior172. The packaging apparatus165is configured to receive viral vaccine73in the dried state77from the collector60and to place the viral vaccine73in the dried state77into the package interior172of one or more packages170. Various material handling and storage mechanisms for the manipulation and/or storage of viral vaccine73in the dried state77may be included with the packaging apparatus165as would be recognized by those of ordinary skill in the art upon review of this disclosure.

Aliquots of the viral vaccine73in the dried state77may be placed into the package interior172of the one or more packages170in such amounts that, when resuspended by the addition of liquid such as sterile buffered saline solution into the package interior172of the package170, the now resuspended viral vaccine73achieves a concentration of viral particle78appropriate for the inoculation of one or more recipients.

The packaging apparatus165may be configured to seal the package170following placement of the viral vaccine73within the package interior172, and the packaging apparatus165may be configured to sterilize the package interior172following placement of the viral vaccine73in the dried state77within the package interior172.

In some aspects, the packaging apparatus165may seal the viral vaccine73in the dried state77within the package interior172of the one or more packages170. Air and/or other gasses may be evacuated from the package interior172so that the viral vaccine73in the dried state77is sealed within the package interior172under substantially vacuum conditions. In some aspects, an inert gas could be placed within the sealed package interior172. The one or more packages170may then be irradiated by, for example, gamma radiation from a gamma source180to sterilize the package interior172. Alternatively, the sealed packages170may be Tyndallized by being subjected to repeated heating and cooling to sterilize the package interior172.

In other aspects, the packaging apparatus165may place the viral vaccine73in the dried state77within the package interior172of the one or more packages170with the one or more packages170unsealed. The package interior172of the one or more packages170may then be exposed to a sterilizing gas such as ethylene dioxide may then be introduced into the package interior172. After a suitable exposure time, the sterilizing gas may be evacuated from the package interior172of the one or more packages170and the one or more packages170sealed. In some aspects, the package interior172may be repetitively exposed to the sterilizing gas prior to the sealing of the package170. Other sterilization techniques could also be employed in various aspects as would be recognized by one of ordinary skill in the art upon review of this disclosure.

In some aspects, the gas stream20may be generated by a pulse combustion dryer30. Examples of pulse combustion dryers30are described in U.S. Pat. Nos. 3,462,995, 4,708,159, 4819,873, and 4,941,820. The pulse combustion dryer30may include a combustor31that defines a combustion chamber32, and a tailpipe40that defines a tailpipe passage42having a first tailpipe passage end44and a second tailpipe passage end46. The tailpipe passage42is in fluid communication with the combustion chamber32through the first tailpipe passage end44.

The pulse combustion dryer30, in some aspects, may include a drying chamber50that defines a drying chamber passage52having a first drying chamber passage end54, a second drying chamber passage end56, and centerline153. The first drying chamber passage end54of the drying chamber50may be disposed with respect to the second tailpipe passage end46of the tailpipe40so that the drying chamber passage52is in fluid communication with the tailpipe passage42, and, thence, in fluid communication with the combustion chamber32. The combustor31, tailpipe40, and drying chamber50may be disposed with respect to one another in a variety of ways and may assume a variety of orientations with respect to the vertical that would be readily recognized by those of ordinary skill in the art upon review of this disclosure.

Combustion air86and fuel84may be admitted into the combustion chamber32, and the resulting fuel-air mixture ignited periodically to provide the gas stream20in the form of a series of pulses of air mixed with heated combustion products. Combustion of the fuel-air mixture may be generally complete so that the heated combustion products would consist largely of carbon dioxide and water vapor. The gas stream20may flow from the combustion chamber32, thru the tailpipe passage42from the first tailpipe passage end44to the second tailpipe passage end46. In aspects that include the drying chamber50, the gas stream20may be communicated from the tailpipe passage42into the drying chamber passage52generally proximate the first drying chamber passage end54, and the gas stream20may flow through the drying chamber passage52generally from the first drying chamber passage end54to the second drying chamber passage end56. Thus, the flow path90of the gas stream20includes the combustion chamber32, the tailpipe passage42, and, in aspects that include the drying chamber50, the flow path90also generally includes the drying chamber passage52. The first end94of the flow path90may be generally coincident with the combustion chamber32.

In aspects wherein the gas stream20is generated by the pulse combustion dryer30, the collector60may be disposed generally proximate the tailpipe passage second end96or, in aspects that include the drying chamber50, generally proximate the second drying chamber passage end56to recover the viral vaccine73in the dried state77. As would be understood by those of ordinary skill in the art upon review of this disclosure, the collector60may be disposed in other ways with respect to the drying chamber50to recover the viral vaccine73in the dried state77from the second end96of the flow path90of the gas stream20.

The viral vaccine73generally in the liquid state75may be introduced into the flow path90of the gas stream20at the introduction location110. In various aspects, the introduction location110may be within the tailpipe passage42or within the drying chamber passage52. The viral vaccine73may be entrained in the gas stream20generally at the introduction location110and dried while being conveyed by the gas stream20along the portion of the flow path90from the introduction location110to the second end96of the flow path90. The viral vaccine73in the dried state77may be recovered at the second end96of the flow path90of the gas stream20by the collector60.

The viral vaccine73in the liquid state75may be introduced into the gas stream20at the introduction location110from one or more passages120through one or more passage outlets122defined by the one or more passages120disposed about the gas stream20at the introduction location110for that purpose. The viral vaccine73may pass through the one or more passages120into the gas stream20by gravity feed and/or by the application of pressures, which may be quite minimal. Pressure pulses in the gas stream20may aid in drawing the viral vaccine73through the passage120and into the gas stream20. Accordingly, the shear forces that the viral vaccine73is subjected to while passing through the passage120may be generally small or negligible. In various aspects, the rate at which viral vaccine73is fed into the gas stream20may be controllable.

In some aspects, nozzles, sprayers, or similar may be appended to the passage120to disperse the viral vaccine73from the passage outlet122into the gas stream20. However, this may not be necessary, as the violence of the flow of the gas stream20may be sufficient to disperse the viral vaccine73including the dispersal of any agglomerations, aggregations, non-homogeneities and/or clumps of materials such as the viral particle78. The shock waves and/or turbulence in the gas stream20may disperse the viral vaccine. Sound waves in the gas stream20may sonicate the viral vaccine73, which may aid in the dispersal of the viral vaccine73into the gas stream20. Pressure pulses in the gas stream20may also aid in the dispersal of the viral vaccine73into the gas stream20.

FIG. 1illustrates by schematic diagram the methods of drying the viral vaccine73in the liquid state75into viral vaccine73in the dried state75using the gas stream20. This Figure depicts the gas stream20flowing along flow path90from the first end94to the second end96. The viral vaccine73in the liquid state75is introduced into the gas stream20at introduction location110as illustrated. The viral vaccine73is dried by the gas stream20while being convected by the gas stream20from the introduction location110to the second end96of the flow path90. The viral vaccine73in the dried state77is recovered from the gas stream20proximate the second end96of the flow path90, the location or locations at which the viral vaccine73in the dried state77is recovered from the gas stream20generally defining the second end94.

An embodiment of the pulse combustion drier30is generally illustrated inFIG. 2A. The embodiment ofFIG. 2Aincludes the combustor31, the tailpipe40, and the drying chamber50. The combustion chamber31fluidly communicates with the tailpipe passage42through the first tailpipe passage end44. The tailpipe40is disposed with respect to the drying chamber50such that the tailpipe passage42fluidly communicates through the second tailpipe passage end46into the drying chamber passage52generally proximate the first drying chamber passage end54, as illustrated. The drying chamber passage52fluidly communicates with the collector60through the second drying chamber passage end56, in this embodiment. In other embodiments, the collector60could be otherwise disposed with respect to the drying chamber50. For example, at least a portion of the collector60could be positioned within a portion of the drying chamber passage52generally proximate the second drying chamber passage end56.

In the embodiment illustrated inFIG. 2A, the gas stream20is generated within the pulse combustion dryer30and the viral vaccine73in the wet state75is dried into the viral vaccine in the dry state75by the pulse combustion dryer30. Fuel84and combustion air86are admitted into the combustion chamber32defined by the combustor31to be ignited periodically in order to produce the gas stream20. An air valve88may be disposed in the path of the combustion air88to admit combustion air88into the combustion chamber32while generally preventing backflows of the gas stream20, as illustrated. As illustrate inFIG. 2A, the flow of the gas stream20from the combustion chamber32, through the tailpipe passage42, through the drying chamber passage52and into the collector69defines the flow path90. The first end94of the flow path90is generally within the combustion chamber32, and the second end96of the flow path90is generally proximate the collector60which is disposed about the second drying chamber passage end56of the drying chamber50in the embodiment illustrated inFIG. 2A.

Viral vaccine73generally in the liquid state75may be introduced into the gas stream20at the introduction location110through the passage outlet122defined by passage120in the embodiment illustrated inFIG. 2A. In this embodiment, a portion of the tailpipe40extends into the drying chamber passage52of the drying chamber50. The introduction location110, in this embodiment, is within the drying chamber passage52generally proximate the tailpipe passage second end46and generally proximate the first drying chamber passage end54. The passage120is disposed within the drying chamber passage52to introduce the viral vaccine into the gas stream20generally proximate the centerline153of the drying chamber passage52in the embodiment ofFIG. 2A.

In other embodiments, a plurality of passages120may be provided. One or more tubes may be disposed within the drying chamber passage42, in some embodiments, to introduce the viral vaccine73into the gas stream20at an off-set from the centerline153. For example, a plurality of passages120may be disposed circumferentially within the drying chamber passage42with each passage120of the plurality of passages120positioned to introduce the viral vaccine73into the gas stream20at a constant radial location with respect to the centerline153.

As illustrated inFIG. 2A, the viral vaccine73introduced into the gas stream20through the passage outlet122may be entrained into the gas stream20to be dried from the liquid state75to the dried state77. The viral vaccine73generally in the dried state77may then be recovered from the gas stream20by the collector60. The collector60is positioned proximate the second drying chamber passage end56and generally defines the second end96of the flow path90, in this illustrated embodiment.

As illustrated inFIG. 2A, one or more additional airflows may be admitted into the drying chamber passage52in various embodiments of the pulse combustion dryer30. In the embodiment ofFIG. 2A, quench air22may be admitted into the drying chamber passage52generally proximate the first drying chamber end54to control the temperature of the gas stream20within the drying chamber passage52. The quantity of quench air22admitted into the drying chamber passage52may be regulated in order to control the temperature of the gas stream20including the first temperature104and the second temperature106. In this embodiment, dilution air24may also introduced into the drying chamber passage52generally proximate the first drying chamber passage end54to provide thermodynamic space for the uptake of water evaporated from the viral vaccine73in order to prevent water condensation and/or saturation conditions in the drying chamber passage52and/or in the collector60. The quantity of dilution air24admitted into the drying chamber passage52may be regulated in various embodiments.

In the embodiment illustrated inFIG. 2A, the gas stream20may pass through a core region155generally proximate the centerline153of the drying chamber passage52. The dilution air24may pass through the wall region159of the drying chamber passage52which is the portion of the drying chamber passage52generally proximate the inner wall53of the drying chamber50. The quench air22may pass through an intermediate region157which is intermediate between the wall region159and the core region155.

Viral vaccine73may be introduced into the gas stream20passing though the core region155. The quench air22and/or the dilution air24may prevent or at least diminish contact between the viral vaccine73and the inner wall53of the drying chamber50as the viral vaccine73is convected through the drying chamber passage42by the gas stream20in order to generally reduce or eliminate deposition of viral vaccine73onto the inner wall53.

FIG. 2Billustrates a cross-section of the drying chamber50. As illustrated, the drying chamber50defines a drying chamber passage52having a substantially circular cross-section. In this embodiment, the flows of the gas stream20, the quench air22, and the dilution air24through the drying chamber passage52generally define three regions within the drying chamber passage. These regions include the core region155generally proximate the centerline153through which the gas stream20generally passes, the intermediate region155through which the quench air22generally passes, and the wall region159through which the dilution air24generally passes. The pulse combustion dryer30may be configured to regulate the amount of quench air22and/or the amount of dilution air24admitted into the drying chamber passage52in order to regulate temperature and other conditions within the drying chamber passage52. In other embodiments, one or more airstreams could be introduced into the drying chamber passage52at various locations about the drying chamber passage52to cool the gas stream20, provide thermodynamic space for evaporation, or for other purposes as would be understood by those of ordinary skill in the art upon review of this disclosure.

The gas stream20has a first temperature104generally proximate the introduction location110, as illustrated inFIG. 2A. The gas stream20has a second temperature106generally proximate the second end96of the flow path90of the gas stream20, as illustrated. In various embodiments, the pulse combustion dryer30may be configured to regulate the amount of additional gas flows such as the quench air22and the dilution air24admitted into the gas stream20to regulate the temperature. In various embodiments, the fuel admitted into the combustion chamber32may be controlled, the pulse rate of the pulse combustion dryer30may be regulated, and/or the pulse combustion dryer30may be configured and/or controlled in other ways to regulate the temperature of the gas stream20including the first temperature104and the second temperature106as would be recognized by those of ordinary skill in the art upon review of this disclosure.

In the schematic diagram ofFIG. 3A, the collector60recovers the viral vaccine73in the dried state77from the gas stream20. The collector60, as illustrated, cooperates with the packaging apparatus165to seal the viral vaccine73in the dried state77within the package interior172of one or more packages170. A gamma source180is provided in this embodiment to irradiate the package interior172and viral vaccine73in the dried state77for sterilization in this embodiment.FIG. 3Billustrates an embodiment of the package170with viral vaccine73in the dried state77sealed within the package interior172.

FIG. 4illustrates schematically an embodiment of the combination of viral particle78and carrier material79to form the viral vaccine73in the dried state77. As illustrated, the viral vaccine73in the liquid state77includes the viral particle78and the carrier material79suspended in water. Upon drying, the viral particle78may be interposed with the carrier material79, as illustrated. Drying the viral vaccine73in the gas stream20may result in the formation of generally spherical particles of viral vaccine73in the dried state77, as illustrated.

EXAMPLES

A further understanding may be obtained by reference to certain specific examples, which are provided herein for the purpose of illustration only and are not intended to be limiting unless otherwise specified.

In example 1, viral particle78in the form of purified attenuated live virus is suspended in buffered aqueous solution with an added carrier material79to form the viral vaccine73in the liquid state75. The concentration of viral particle78(i.e. attenuated live virus particles) is about 0.1% to about 5.0% solids by weight with a preferred concentration of about 1.5% to about 3.0%. The pH of the buffered solution is between about 5.5 and about 8.5, and in some embodiments has a pH range of about 6.5 to about 7.5. The buffer concentration is between about 10 mM and about 200 mM, and in some embodiments has a concentration of about 20 mM to about 70 mM, and the buffer is compatible with an injectable medical solution such as, for example, potassium phosphate buffer. The concentration of carrier material79is about 2.5% to about 30% solids by weight, and in some embodiments has a concentration of about 10.0% to about 20% solids by weight. The carrier material79acts to bulk up the viral vaccine73in the dried state77and to protect the viral particle78from damage during the drying process. The carrier material79is biologically compatible with use in an injectable medical solution, for example, sugar such as glucose, lactose, or trehalose, or other suitable material.

The viral vaccine73in the liquid state75including the buffered aqueous solution of attenuated live virus particles, buffer and carrier is dried using a pulse combustion spray drier (for example a Pulse Combustion Systems Model P-0.3) in this example. The viral vaccine73in the liquid state75is conveyed to the drying chamber50using a sanitary system of pumps and hoses where the viral vaccine73in the liquid state75is introduced into the gas stream20within the pulse combustion dryer30at the introduction location110through one or more passages120adapted for that purpose. The first temperature104of the gas stream20generally proximate the introduction location110is between about 700° F. and about 1300° F., and in some embodiments has a temperature range of 750° F. and 850° F. The second temperature106generally proximate the second drying chamber passage end56is between about 135° F. and about 250° F., and in some embodiments has a range of about 140° F. to about 180° F. The feed rate at which the viral vaccine in the liquid state75is introduced into the gas stream is adjusted to maintain the second temperature106within the desired range.

The viral vaccine73in the dried state77containing live attenuated virus with buffer and carrier is conveyed from the second drying chamber passage end56pneumatically to the collector60in example 1. The collector60, in example 1, is a cyclone precipitator, a sanitary bag house, or other appropriate method for capturing the viral vaccine73in the dried state77in a sanitary fashion. The viral vaccine73in the dried state77has a particle size of between about 1 and about 100 microns, and in some embodiments ranges from about 1 to about 20 microns. The moisture content of the powder is between about 0.5% and about 10%, and in some embodiments ranges from about 0.5% to about 3.0%. The activity of the viral vaccine73in the dried state77is defined, in this example, as the viral particle viability in the viral vaccine73in the dried state77, which is generally greater than 30%, and in some embodiments is generally greater than 90% of the viability of the viral particles in the liquid state before drying.

In example 1, the viral vaccine73in the dried state77is portioned into sanitary packages170sized to serve the end user. Material intended for use in mass inoculation programs will be in larger packages170than material intended for individual inoculations. The packages170may be sealed and crimped before being subjected to sterilization by irradiation, for example gamma irradiation. Alternatively the packages170may be partially stoppered and subject to gas sterilization, for example using ethylene dioxide gas, before being sealed and crimped.

In example 1, the end product is a vial170containing sterile viral vaccine73in the dried state77suitable for use in human and/or animal health applications.

Purified viral particles78including inactivated virus and constituent parts are suspended in buffered aqueous solution with an added carrier material79. The concentration of virus material is 0.1% to 5.0% solids by weight, and in some embodiments have a concentration of 1.5% to 3.0%. The pH of the buffered solution is between 5.5 and 8.5, and in some embodiments, is between 6.5 to 7.5. The buffer concentration is between 10 mM and 200 mM with, and in some embodiments has a concentration of 20 mM to 70 mM. The buffer used is compatible with an injectable medical solution, for example potassium phosphate buffer. The concentration of carrier material79is 2.5% to 30% solids by weight with a preferred concentration of 10.0% to 20%. The carrier material79acts to bulk up the final viral vaccine73in the dried state77and to protect the virus particles78from damage during the drying process. The carrier material79is biologically compatible with use in an injectable medical solution, for example, glucose, lactose, trehalose, or other suitable material.

The viral vaccine73in the liquid state75is conveyed to the drying chamber50using a sanitary system of pumps and hoses where the viral vaccine73in the liquid state75is introduced into the gas stream20within the pulse combustion dryer30at the introduction location110through one or more passages120adapted for that purpose. The temperature of gas stream20generally proximate the introduction location110is between about 700° F. and about 1300° F., and in some embodiments is between about 750° F. and 850° F. The second temperature106generally proximate the second drying chamber passage end56is between about 135° F. and 250° F., and in some embodiments has a range of about 140° F. to 180° F. The feed rate of the viral vaccine73in the liquid state75into the gas stream20is adjusted to maintain the second temperature106within the desired range.

The viral vaccine73in the dried state77containing virus particles78that include inactivated virus and constituent parts with buffer and carrier is conveyed pneumatically from the second drying chamber passage end56to the collector60. The collector60in example 2 is a cyclone precipitator, a sanitary bag house, or other appropriate method for capturing the dried powdered material in a sanitary fashion. The viral vaccine73in the dried state77has a particle size of between 1 and 100 microns, and in some embodiments the particle size is between about 1 and 20 microns. The moisture content of the viral vaccine73in the dried state77is between about 0.5% and 10%, and in some embodiments ranges from about 0.5% to 3.0%. The activity of the viral vaccine73in the dried state77is defined, in this example, as the antigenic potency of the virus particles78. In this example, the virus particles78retain at least about 30% of their antigenic potency, and in some embodiments have greater than about 90% of the antigenic potency as they had in the liquid state before drying

In example 2, the viral vaccine73in the dried state77is portioned into sanitary packages170sized to serve the end user. Material intended for use in mass inoculation programs will be in larger vials than material intended for individual inoculations. The vials may be sealed and crimped before being subjected to sterilization by irradiation, for example gamma irradiation. Alternatively they may be partially stoppered and subject to gas sterilization, for example using ethylene dioxide gas, before being sealed and crimped. The end product is a sterile vaccine suitable for use in human and animal health application.

The foregoing discussion discloses and describes merely exemplary embodiments. Upon review of the specification, one of ordinary skill in the art will readily recognize from such discussion, and from the accompanying figures and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.

All publications, patent publications and applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.