Vaccine and Pharmaceutical Formulation and Stabilization Technologies

Fast-dissolving tablet formulations

Meeting the challenge

Diarrheal disease is the second leading killer of children under the age of five worldwide, responsible for approximately 1.3 million child deaths annually. It results from exposure to rotavirus as well as bacterial pathogens such as cholera, enterotoxigenic E. coli (ETEC), and Shigella, among others. A number of live-attenuated oral vaccines containing multiple bacterial strains are in development, giving hope to those that live in ETEC- and Shigella-endemic countries.

To obtain adequate heat stability, these candidate liquid vaccine formulations must be lyophilized (freeze dried), necessitating their reconstitution at the point of use. In this scenario, because the relevant bacterial strains are often incompatible, multiple vials containing each lyophilized strain would be required alongside a vial for the diluent and a reconstitution syringe to combine them—increasing costs, cold chain space requirements, preparation complexity, and the risk of error.

Novel technology solution

To address the potential challenges and costs associated with the complex production, storage, transport, and reconstituted delivery of these important vaccines, PATH has worked to apply existing fast-dissolving tablet (FDT) technologies to a trivalent candidate ETEC vaccine. Manufactured using a standard lyophilization process, our lead ETEC FDT formulation is stable at 12 months under refrigeration. Ongoing work has also produced an ETEC FDT formulation that is stable at ambient temperatures, with maintained viability for at least 3 months.

There are two potential means of delivering the ETEC vaccine tablets. When placed in the mouth, the small tablet disintegrates instantly in a modest amount of saliva, removing the risk of choking and making it safe for use in young children. The tablets can also be reconstituted in a diluent or buffer without need for a reconstitution syringe and then administered orally using a liquid dropper.

Value-added product presentation

Each tablet can be packaged in unit-dose blisters made from foil or other pharmaceutical-grade material, offering an inexpensive, scalable, and easy-to-use product presentation for live-attenuated vaccines containing single or multiple bacterial strains. Due to less expensive packaging material and an increased throughput achieved by lyophilizing smaller volumes, the tablet vaccines may prove to be less expensive to produce than lyophilized vaccines in glass vials. In addition, the stackable product presentation may minimize product volume and thus the space required for storage and transport, resulting in significant savings from a health system and cold chain capacity perspective.

Veterinary vaccine application

PATH has applied the FDT technology to other vaccines, including a veterinary vaccine that protects against Newcastle disease (ND), one of the biggest threats to poultry and the livelihoods of the rural poor globally. Commissioned by the Global Alliance for Livestock Veterinary Medicines, PATH developed a fast-dissolving ND vaccine tablet to facilitate the immunization of “backyard poultry” in developing countries—with the goal of improving stability, enabling dosing size flexibility, and expanding vaccine coverage and impact in low-resource rural settings. Additional technical collaborators on the work included the Southeast Poultry Research Laboratory of the US Department of Agriculture and the University of Washington.

Our journal article detailing the development of a heat-stable FDT formulation of ND vaccine was published in Veterinary Record and awarded the 2014 William Hunting Award, which is bestowed annually by the British Veterinary Association to a research paper considered to have made the most useful contributions to veterinary science. Read this PATH blog profile to learn more about this exciting achievement »

With our partners, we continue to explore the feasibility of producing ND vaccine tablets using equipment and materials that developing-country manufacturers already have or can easily and inexpensively access. Please contact us for more information on available technology transfers.

Potential drug applications

Oxytocin tablets. Currently, the prevention and treatment of postpartum hemorrhage (PPH) or excessive bleeding after childbirth requires an intramuscular injection or intravenous infusion of oxytocin, a drug that reduces bleeding by causing the uterus to contract. To more easily and effectively prevent and treat PPH in developing countries, where 99 percent of the global burden of maternal mortality resulting from PPH occurs, PATH is working to develop heat-stable, fast-dissolving oxytocin tablets for sublingual delivery.

The easy-to-use, heat-stable tablet format will enable traditional birth attendants and midwives to safely and effectively administer oxytocin with little to no training, expanding access to oxytocin in areas lacking formal health care facilities and reliable power for refrigeration. Its needle- and device-free presentation will also eliminate the risks associated with sharps use and disposal. In addition, the tablet’s compact blister packaging will simplify shipping, storage, and distribution logistics—helping to reduce costs for public health programs.

In collaboration with the South African Medical Research Council, pharmacokinetic evaluations of PATH’s fast-dissolving oxytocin tablet are scheduled to commence in 2016.

Tenofovir tablets. A number of antiretroviral medications exist for the treatment and prevention of HIV infection, including tenofovir, a drug indicated for adults and pediatric patients 2 years old or older. Tenofovir is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years or older.

In collaboration with CONRAD, PATH scientists are working to develop an easy-to-use, single-dose, fast-dissolving microbicide tablet formulation of tenofovir for vaginal mucosal delivery. Like oxytocin tablets, an inexpensive needle- and device-free presentation of tenofovir will enable the safe and effective administration of the drug with little to no preparation, training, or instruction. The tablet’s compact packaging will also reduce system costs by easing logistics. Altogether, such product attributes hold promise for increasing access to the drug and maximizing its public health impact in low-resource settings.

Additional information