Vitamin K in micelles promise an alternative to injections

Oral administration to prevent brain hemorrhage in infants with vitamin K deficiency

Vitamin K packed in tiny spheres may help prevent severe bleeding in babies. Researchers have now taken an important step in developing this method, bringing an alternative to injections with vitamin K closer to reality. The researchers are affiliated with Utrecht University, the University Medical Center Utrecht, and the pharmaceutical company Tiofarma.

Vitamin K is essential for properly functioning blood coagulation. However, newborn babies often have low levels of vitamin K in their blood. During pregnancy, only limited amounts of the vitamin are transferred to the unborn child. To prevent vitamin K deficiency, newborn babies are therefore given extra vitamin K in the diet.

Vitamin K deficiency usually doesn't come into view until the bleeding has already occured

However, this is not sufficient for babies who have difficulty absorbing fatty substances due to a liver problem. Vitamin K is a very fatty substance, and a deficiency of it can occur in babies with impaired fat absorption. The deficiency can lead to severe bleeding, including brain hemorrhage. Problems with fat absorption, however, usually do not come into view until the bleeding has already occurred.

Advice for injections

Currently, Vitamin K is still administered to babies as oral drops, but the effect of this is limited. Brain hemorrhages in babies are still relatively frequent in the Netherlands. The Health Council of the Netherlands therefore recommended in 2017 that vitamin K be administered via injections. Last week, the Dutch State Secretary Paul Blokhuis announced that he would follow the advice. His decision means that all newborns in The Netherlands will receive a one-time vitamin K injection right after birth, starting in mid-2022.

We are now showing that alternatives to injections do exist

“We are now showing that alternatives to injections do exist,” says Thijs Rooimans, PhD student at Utrecht University. “People simply don’t like injections. In addition, it is simply not always possible to administer injections.”

Extremely fatty

The absorption of vitamin K in the body is complex, because it is an extremely fatty substance that dissolves poorly in water. It always needs a helping compound to be absorbed properly. The compound comes from bile, which is excreted in the intestine. The substance and takes up vitamin K in tiny spheres, also called micelles. Thanks to the micelles, the body can absorb vitamin K.

Exactly these excipients are missing when fat absorption is impaired. One solution to this would be to administer vitamin K and the excipients orally in the form of micelles. But the problem is that the excipients from the bile then suddenly must pass through the stomach, where stomach acids damage the micelles beyond repair.

The researchers 'prepackaged' vitamin K into micelles made from bile salts that are also produced in our bodies.

Molecular garlands and bile salts

The researchers found two solutions to that problem. The first step was to ‘prepackage’ vitamin K into micelles made from bile salts that are also found in our bodies. The researchers found a composition of bile salts that is resistant to stomach acid. Micelles of these bile salts remain intact in the stomach, delivering the packaged vitamin K to the intestines.

In addition, they applied a type of molecular garlands to the outside of micelles. This prevents the micelles from clumping together.

Reliable and stable absorption

In the journal Gastroentorology, the researchers show that their approach works in laboratory animals with impaired fat absorption. “When you regard both solutions separately, they are about equally effective,” says Peter van Hasselt, researcher at UMC Utrecht. “But when you combine the two, the absorption of vitamin K in the body becomes more stable and reliable. The combined effect is great enough to get sufficient vitamin K levels in the blood.”

Suitable for cancer drugs?

According to the researchers, their method also offers good prospects for other fatty drugs. “We are now investigating if our method also works for an anti-cancer drug,” said Rene van Nostrum, researcher at Utrecht University. “The question now is, can we wrap the drug, will it be stable then, and do the micelles reach the intestines?”

We are currently investigating if our method also works for an anti-cancer drug

Van Hasselt: “There are still a lot of fatty drugs sitting in the waiting room. These drugs don’t reach the final stages of development yet, because they are difficult to get into the body. It is therefore obvious to see if our method can also be applied to this group of medicines.”


Novel Orally Formulated Mixed Micelles Optimize Vitamin K Absorption Under Bile Deficient Conditions

Gastroentorology, 2 juni 2021 DOI: 10.1053/j.gastro.2021.05.056

T. Rooimans*, T.C. Minderhoud, N. Leal, M. Rodriguez, F. Sun*, C. Oussoren*, T.K. Slot*, M. van der Ham*, G.E.P.J. Janssens*, M.G.M. de Sain-van der Velden*, R.H.J. Houwen*, T.J. de Koning, W.E. Hennink*, H. Vromans* , C.F. van Nostrum*, P.M. van Hasselt*

* = Researcher at Utrecht University