Ionizing irradiation sterilization of bacterial minicell-based biopharmaceuticals and methods of use
Inventors
Giacalone, Matthew J. • Ward, Gary H.
Assignees
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Publication Number
US-11564953-B2
Publication Date
2023-01-31
Expiration Date
Abstract
Disclosed herein are methods of terminally sterilizing bacterial minicells or compositions comprising bacterial minicells by exposure to ionizing irradiation. Also disclosed are terminally sterilized bacterial minicells, pharmaceutical compositions comprising the bacterial minicells, and methods of use the bacterial minicells and pharmaceutical compositions.
Core Innovation
The disclosure describes terminal sterilization of bacterial minicell-based biopharmaceuticals by exposing bacterial minicells, or compositions containing bacterial minicells, to ionizing irradiation. The pharmaceutical composition is rendered sterile to a level conforming to USP <71> standards under USP 38 NF 33 while preserving bacterial minicell integrity, and the terminal sterilization is preferably gamma irradiation.
The disclosure states that exposing bacterial minicells to ionizing irradiation maintains stability and preserves targeting moieties and payload bioactivity. In particular, it describes maintenance of invasin properties, including invasin or invasin equivalents, after gamma irradiation and preservation of functional activity associated with payloads such as perfringolysin O activity.
The disclosure further provides sterile pharmaceutical composition formulations containing a plurality of bacterial minicells exposed to ionizing irradiation. The disclosure describes formulations using pharmaceutically acceptable excipients such as trehalose in sterile water, and presentation forms including frozen suspension and frozen lyophile (lyophilized), with examples reporting preserved anti-tumor activity in an MB49 orthotopic bladder cancer model and additional stability and integrity observations for targeted minicells carrying doxorubicin and EGFR-1 targeting.
Claims Coverage
The independent claim covers a sterile pharmaceutical composition that contains a plurality of bacterial minicells exposed to ionizing irradiation, with sterility conforming to USP <71> standards under USP 38 NF 33. The inventive features include six refinements across irradiation type, minicell origin, displayed targeting moiety, excipient, and formulation form.
Irradiated bacterial minicell sterile pharmaceutical composition
A pharmaceutical composition comprising a plurality of bacterial minicells exposed to ionizing irradiation, wherein the pharmaceutical composition is sterile to a level conforming to USP <71> standards under version USP 38 NF 33.
Gamma irradiation for terminal sterilization
The pharmaceutical composition in which the bacterial minicells have been exposed to gamma irradiation.
Bacterial minicells derived from specified genera
The pharmaceutical composition in which the bacterial minicells are derived from bacteria belonging to specified genera including Escherichia, Salmonella, Listeria, Pseudomonas, Acinetobacter, Neiserria, Shigella, Bacillus, or Haemophilus.
Invasin or functional equivalent display
The pharmaceutical composition includes bacterial minicells that display invasin or a functional equivalent of invasin.
Trehalose as pharmaceutically acceptable excipient
The pharmaceutical composition wherein the pharmaceutically acceptable excipient is trehalose.
Frozen suspension or frozen lyophile formulation
The pharmaceutical composition formulated as either a frozen suspension or a frozen lyophilized (lyophile) preparation.
Across the independent claim and dependent refinements, the claim coverage centers on a USP <71>-sterile pharmaceutical composition comprising irradiated bacterial minicells, further defined by gamma irradiation, specified bacterial genera, invasin display, trehalose excipient, and frozen suspension or frozen lyophile formulation.
Stated Advantages
Provides a sterile pharmaceutical composition conforming to USP <71> standards under USP 38 NF 33.
Preserves bacterial minicell integrity after terminal sterilization with ionizing irradiation.
Maintains stability and preserves targeting moieties such as invasin or invasin equivalents after gamma irradiation.
Preserves payload bioactivity, including maintenance of perfringolysin O activity.
Maintains anti-tumor activity in an MB49 orthotopic bladder cancer mouse model after gamma irradiation.
Documented Applications
Terminal sterilization of bacterial minicell-based biopharmaceuticals by exposing bacterial minicells, or compositions containing them, to gamma or ionizing irradiation while preserving sterility and minicell functional properties.
Use of irradiated, sterile minicell pharmaceutical compositions preserving targeting, including invasin or invasin equivalents and EGFR-1 targeting, for anti-tumor activity in an MB49 orthotopic bladder cancer model.
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