Researchers may have figured out a way to make an antiretroviral drug with undesirable side effects more tolerable for babies and young children with HIV/AIDS.
The new method, which alters a protein in milk to bind with the drug, promises to greatly improve treatment for the estimated 3.4 million children living with HIV/AIDS. Nine out 10 of them live in resource-limited countries in sub-Saharan Africa, where effective antiretroviral treatments are still not widely accessible or available.
International medical experts believe less than a third of affected children worldwide receive an antiretroviral drug.
Most antiretroviral drugs are not well tolerated by very young children. One of the most commonly prescribed antiretroviral drugs for treating and preventing HIV infection, Ritonavir, has undesirable side effects and important oral-delivery problems. Its physicochemical properties challenge its administration to infants, says Federico Harte, associate professor of food science at Penn State.
“Ritonavir has a high hydrophobicity and low solubility in water, which lead to a low dissolution rate in the gastrointestinal fluid and, hence, to insufficient bioavailability. The liquid formulation used to treat infants over one month of age contains 43 percent ethanol and has an awful flavor that has been described as bitter-metallic, medicinal, astringent, sour, and burning.
“Moreover, when coming into contact with the stomach mucosa, Ritonavir causes nausea, vomiting, and diarrhea. Therefore, we need to develop alternative pediatric formulations of Ritonavir and overcome its poor water solubility to improve its oral administration to infants and children.”
To solve that problem, researchers looked to a group of proteins in cow’s milk called caseins.
Casein proteins form spherical aggregates called casein micelles, which are responsible, incidentally, for the white color of milk. The casein micelles in mammals’ milk are natural delivery systems for amino acids and calcium from the mother to her baby, and researchers thought they might deliver Ritonavir molecules as well.
Milk powder transport
“I have been working with bovine casein micelles for a few years now, and we have investigated the structure and functionality of these proteins,” Harte says. “What we found is these micelles are able to carry molecules that have very little solubility in water, that have low molecular weight, and that are very hydrophobic—such as Ritonavir.”
The research shows that subjecting milk to ultrahigh-pressure homogenization enhances the binding properties of the casein micelles. Previous studies have shown casein micelles could be bound to triclosan—an antimicrobial used in deodorants—and vitamin D, which is added regularly to skim milk.
Normal milk is homogenized at 10 to 15 megapascals. Milk in the new research was homogenized at between 400 and 500 megapascals, disassociating the casein micelles and improving the protein’s binding qualities to attach to drug molecules.
“As a result of this enhanced binding of molecules, we believe a milk powder containing Ritonavir can be used as baby formula, providing a transport system for a drug that is not very soluble in water. Right now we are running tests, and we are in the final stages of an experiment in which we gave three different formulations to piglets,” Harte says.
“We are taking blood serum samples every three hours to study the kinetics of the drug in the piglets. The hope is that—and we don’t have the data yet—we find that the Ritonavir is being adequately delivered by the protein in milk. So if that works, I think we are pretty close to having a formulation that can be used with hydrophobic drugs.”
The National Institutes of Health supported this work.
Source: Penn State