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Stable Frozen Virus Formulation

a technology of virus and formulation, which is applied in the direction of viruses/bacteriophages, drug compositions, dsdna viruses, etc., can solve the problems of increased manufacturing, storage and transportation costs, lack of thermostability, and sub-optimal process yields

Inactive Publication Date: 2017-12-21
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a live virus composition that can be used to kill tumor cells in a patient. The composition includes a herpes simplex virus, a protein, at least one sugar, sodium chloride and sodium phosphate. The composition can be thawed and stored at temperatures between -25°C and -80°C. The live virus composition can be administered to a patient in need thereof, either alone or in combination with a check point inhibitor. The tumor cells that can be targeted include astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, medulloblastoma, melanoma cells, pancreatic cancer cells, prostate carcinoma cells, breast cancer cells, and others.

Problems solved by technology

Live viruses, such as herpes simplex virus, are typically unstable for extended periods of time at storage temperatures higher than −80° C. Lack of thermo-stability poses a challenge for such viruses, particularly for therapeutic viruses in a liquid formulation.
The lack of thermo-stability poses operational challenges that increase the cost of manufacture, storage and transportation.
During manufacturing operations, for example, freeze / thaw cycles could lead to sub-optimal process yields and lack of necessary flexibility in the supply chain.
Storage and transportation are also challenging resulting in complicated handling and complex supply chains.
The lack of thermo-stability also poses commercial challenges.
Live virus compositions that require −80° C. storage to insure stable shelf life lead to complex storage and handling protocols for health care providers.
Such limitations increase the risk of product returns if stored incorrectly or if the entire product is not used.
This has the potential to increase cost to the customer.

Method used

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  • Stable Frozen Virus Formulation
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  • Stable Frozen Virus Formulation

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0116]A formulation containing porcine partially hydrolyzed gelatin (phGelatin) was developed for use with oncolytic viruses. This formulation protects oncolytic viruses against loss in infectivity during long-term storage under frozen conditions, multiple freeze / thaw cycles and liquid storage at 2-8° C. and 25° C. In addition, the formulation reduced formation of both visible and subvisible particles compared to a formulation without phGelatin. This formulation provides advantages over a formulation without phGelatin during manufacturing, packaging and labeling and greatly increases convenience and flexibility to the health care provider.

Sample Preparation

[0117]In this example, the oncolytic herpes simplex virus (HSV-1) talimogene laherparepvec (Lui et al., (2003) Gene Therapy, 10:292-303) was used at concentrations of 106 PFU / mL and 108 PFU / mL. For virus concentration at 108 PFU / mL, samples were prepared by the addition of concentrated excipient stock solutions (i.e. 10-20% w / v ph...

example 2

Protein Concentration

[0140]The combination of improved freeze / thaw and liquid stability would provide substantial advantage for manufacturing, packaging and labeling. The ability to store at 2-8° C. would provide greatly improved flexibility and convenience to the health care providers.

[0141]The control formulation was maintained with the addition of 1%, 2% or 4% phGelatin or 1%, 2% or 4% rHSA. Samples were prepared at 106 PFU / ml. Infectivity (Titer) was determined by plaque assay as described above. The samples were subjected to 5 freeze / thaw cycles as described above.

[0142]The concentration of rHSA and phGelatin was varied to determine the effect of protein concentration on oncolytic HSV-1 stability. Both phGelatin and rHSA provided protection during freeze / thaw cycles over the entire range tested, see FIG. 5.

[0143]The effect of varying protein concentrations on oncolytic HSV-1 liquid stability at 2-8° C. and 25° C. was then tested. The control formulation was maintained with the ...

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Abstract

A live virus composition that maintains infectivity and provides improved virus stability during one or more freeze / thaw cycles and / or during long term storage in a liquid state at temperatures ranging from just above freezing to ambient temperatures.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. 119(e) of U.S. patent application No. 62 / 093,663, filed Dec. 18, 2014, which is incorporated herein by reference.BACKGROUND[0002]Live viruses, such as herpes simplex virus, are typically unstable for extended periods of time at storage temperatures higher than −80° C. Lack of thermo-stability poses a challenge for such viruses, particularly for therapeutic viruses in a liquid formulation. Such therapeutic virus compositions must be stored and transported frozen and used soon after thawing to maintain their therapeutically effective infectivity.[0003]The lack of thermo-stability poses operational challenges that increase the cost of manufacture, storage and transportation. During manufacturing operations, for example, freeze / thaw cycles could lead to sub-optimal process yields and lack of necessary flexibility in the supply chain. Storage and transportation are also challenging resulting ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/763C12N7/00
CPCA61K35/763C12N2710/16632C12N2710/16621C12N7/00A61P35/00
Inventor LITOWSKI, JENNIFER R.SISKA, CHRISTINE CLAUDIAKERWIN, BRUCE ARTHUR
Owner AMGEN INC