Innovative Science Overcomes Formulation Challenges | SRI International

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Innovative Science Overcomes Formulation Challenges

In the event of unexpected, mass radiation exposure—such as that associated with a nuclear accident or terrorist attack—contaminated people must be treated within 24 hours to prevent serious, life-threatening health effects, which includes ingestion or inhalation of carcinogenic radionuclides. A number of agents that remove radioactive isotopes from the body (decorporation agents) are approved to treat radiation and radionuclide contamination, but they are highly impractical for use in mass-casualty situations because they must be delivered intravenously on a daily basis for weeks or months.

Using innovative science to overcome formulation challenges, SRI Biosciences has developed and successfully manufactured a new oral formulation of Zn-DTPA, one of the earliest oral forms amongst decorporation agents, and is advancing the product into human clinical studies. SRI has received U.S. Food and Drug Administration (FDA) clearance for an Investigational New Drug (IND) application to conduct human clinical testing to evaluate safety, tolerability and pharmacokinetics in healthy volunteers.

Leveraging SRI’s extensive expertise in developing new formulations

The chemical compound zinc diethylenetriaminepentaacetate (Zn-DTPA) has been used for many years as an antidote to radionuclide exposure. Previous attempts to re-formulate Zn-DTPA from an IV medication into an oral formulation were hampered by formulation challenges – particularly due to unacceptable intestinal permeation – as well as the requirement for room temperature stable product.

In 2005, the U.S. National Institutes of Health issued a request for new ideas to treat individuals affected in radiation-related, mass-casualty situations. SRI Biosciences received NIH funding for a project to develop an effective, novel oral formulation of Zn-DTPA. The project required SRI to complete proof of concept studies and identify orally-bioavailable formulation candidates, and then conduct pharmacokinetic profiling, efficacy studies, manufacturing and stability testing.

SRI Biosciences applied its innovative “IVtoPO Platform Technology” program to identify promising “permeation enhancers” that could be combined with Zn-DTPA to create an orally available formulation of the drug. The IVtoPO platform harnesses SRI’s advanced formulation tools based on high-throughput screening strategy as a way to develop new oral formulations for already-approved IV products. Researchers used a robotically controlled, automatic screening system to complete both high-throughput solubility screening and intra-intestinal permeation through live tissue. This technology is ideal for most drugs that have poor or moderate oral bioavailability.

Field trials to test and define human efficacy of a DTPA product are not ethically feasible, so SRI designed a development plan that includes well-controlled animal efficacy and safety studies per the FDA’s Animal Efficacy Rule. This plan enabled SRI to significantly accelerate the development of its oral DTPA compound.

A new option for treating radiation exposure

SRI Biosciences developed and successfully manufactured a novel, oral formulation of Zn-DTPA that could be self-administered by people affected in radiation-related, mass-casualty situations. In the first quarter of 2017, the U.S. Food and Drug Administration cleared an Investigational New Drug application for Phase 1 clinical studies to test the oral product in healthy human subjects. Following successful completion of the Phase 1 study, SRI will be able to submit a New Drug Application (NDA) to the FDA.

Research and development activities described were supported by:

National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Contract Number HHSN272201000029C.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.