Preservation by vaporization
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Publication Number
US-9469835-B2
Publication Date
2016-10-18
Expiration Date
Abstract
Significant research is being done to develop and improve delivery mechanisms for biopharmaceuticals and vaccines, including pulmonary (inhalation), nasal, transdermal, and oral alternatives. Market projections indicate that the delivery of proteins and vaccines by inhalation and oral formulation has become and will continue to be increasingly important. These delivery mechanisms, to be effective, will require better stabilization of the biologicals so that they can maintain potency and effectiveness at ambient temperatures for extended periods of time. The novel Preservation by Vaporization (PBV) Technology described herein provides cost-effective and efficient industrial scale stabilization of proteins, viruses, bacteria, and other sensitive biologicals, thereby allowing a production of products that are not possible to be produced by existing methods. The suggested new PBV process comprises primary drying under vacuum from a partially frozen state (i.e. slush) at near subzero temperatures followed by stability drying at elevated temperatures (i.e., above 40 degrees Celsius). The new suggested method can be performed aseptically in unit doze format (in vials) and/or in bulk format (in trays, bags, or other containers). The drying can be performed as a continuous load process in a manifold vacuum dryer comprising a plurality (e.g., 30) of vacuum chambers attached to a condenser during the drying.
Core Innovation
Preservation by Vaporization (PBV) is described as an ambient-temperature stabilization technology for biopharmaceuticals, including vaccines and other labile biologicals. The disclosure preserves therapeutically active biologicals by partially freezing a suspension to obtain a slush comprising a mixture of ice crystals and a liquid between the ice crystals. PBV then uses primary drying conditions intended to vaporize liquid while preventing or inhibiting splattering or eruption, yielding a mechanically stable foam that can optionally include a skim of a thin freeze-dried cake.
In PBV, primary drying is performed under conditions applying temperatures above -20°C and a vacuum pressure below 3 Torr so the liquid boils and the ice crystals sublime. The disclosure then performs secondary drying by desorbing water from the mechanically stable foam under high vacuum at ambient temperature or above. Secondary drying increases the foam’s glass transition temperature to provide preserved therapeutically active biologicals in a glassy matrix stable at ambient temperatures, and the biologicals are not subjected to temperatures equal to Tg' or below.
The disclosure contrasts PBV with freeze-drying (lyophilization) and describes PBV as enabling long-term ambient storage without requiring a cold chain. The disclosure also addresses scale-up limitations of conventional processes and proposes industrial continuous-load manifold vacuum equipment with multiple vacuum chambers connected to a condenser. Reported feasibility and quality results include preserved enveloped viral vaccine with no activity loss after PBV and 1-month storage at 40°C, and preserved enzymes and ice nucleating proteins with no activity loss.
Claims Coverage
The document provides two independent claims: clm-00001 and clm-00015. Each independent claim includes multiple inventive features centered on the PBV preservation sequence, including slush formation, primary drying that prevents splattering, and secondary drying to form an ambient-stable glassy matrix while avoiding temperatures equal to Tg' or below.
Slush formation by partial freezing above -20°C
Partially freezing a suspension comprising one or more therapeutically active biologicals, one or more protective excipients, and an aqueous solution by cooling to a temperature above -20°C to obtain a slush comprising a mixture of ice crystals and a liquid between the ice crystals.
Primary drying that prevents splattering while vaporizing
Performing primary drying of the slush under conditions to prevent or inhibit splattering of the liquid to provide a mechanically stable foam optionally comprising a skim of a thin freeze-dried cake.
Primary drying conditions with temperatures above -20°C and vacuum below 3 Torr
The conditions comprise applying temperatures above -20°C and a vacuum pressure below 3 Torr so the liquid boils and the ice crystals sublime.
Secondary drying to raise glass transition and create an ambient-stable glassy matrix
Performing secondary drying by desorbing water from the mechanically stable foam under high vacuum at ambient temperature or above to increase the foam’s glass transition temperature to provide preserved therapeutically active biologicals in a glassy matrix stable at ambient temperatures.
Avoiding temperatures at or below complete-solidification temperature Tg'
The biologicals are not subjected to temperatures equal to Tg' or below, wherein Tg' is the temperature at which the suspension completely solidifies during cooling.
Scalable PBV sequence including secondary drying continued to >40°C
Continuing the secondary drying at temperatures greater than 40°C to provide preserved therapeutically active biologicals in a glassy matrix that is stable at ambient temperatures for long term storage.
Overall, the independent claims define PBV preservation by forming an ice/liquid slush above -20°C, performing primary drying under temperature and vacuum conditions that prevent or inhibit splattering while enabling boiling and sublimation, and then performing secondary drying under high vacuum to raise glass transition temperature and produce a glassy matrix stable at ambient temperatures for long-term storage. Both independent claims also require that the biologicals are not subjected to temperatures equal to Tg' or below.
Stated Advantages
Provides preserved therapeutically active biologicals in a glassy matrix stable at ambient temperatures for long term storage.
Prevents or inhibits splattering of the liquid during primary drying.
Enables ambient-temperature stabilization without requiring a cold chain.
Preserved biologicals show no activity loss in reported feasibility and quality results, including enveloped viral vaccine, enzymes, and ice nucleating proteins.
Documented Applications
Preservation of an enveloped viral vaccine with no activity loss after PBV and 1-month storage at 40°C.
Preservation of enzymes and ice nucleating proteins with no activity loss.
Preservation and processing in illustrative examples including INB bacteria, enzyme preservation, and alginate hydrogel, powder, and probiotic work.
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